Ovarian function and endocrine phenotypes of lactating dairy cows during the estrous cycle are associated with genomic-enhanced predictions of fertility potential.

The objectives of this prospective cohort study were to characterize associations among genomic merit for fertility with ovarian and endocrine function and the estrous behavior of dairy cows during an entire nonhormonally manipulated estrous cycle. Lactating Holstein cows entering their first (n = 82) or second (n = 37) lactation had ear-notch tissue samples collected for genotyping using a commercial genomic test. Based on genomic predicted transmitting ability values for daughter pregnancy rate (gDPR), cows were classified into high (Hi-Fert; gDPR > 0.6, n = 36), medium (Med-Fert; gDPR -1.3 to 0.6, n = 45), and low fertility (Lo-Fert; gDPR < -1.3, n = 38) groups. At 33 to 39 DIM, cohorts of cows were enrolled in the Presynch-Ovsynch protocol for synchronization of ovulation and initiation of a new estrous cycle. Thereafter, the ovarian function and endocrine dynamics were monitored daily until the next ovulation by transrectal ultrasonography and concentrations of progesterone (P4), estradiol, and FSH. Estrous behavior was monitored with an ear-attached automated estrus detection system that recorded physical activity and rumination time. Overall, we observed an association between fertility group and the ovarian and hormonal phenotype of dairy cows during the estrous cycle. Cows in the Hi-Fert group had greater circulating concentrations of P4 than cows in the Lo-Fert group from d 4 to 13 after induction of ovulation and from day -3 to -1 before the onset of luteolysis. The frequency of atypical estrous cycles was 3-fold greater for cows in the Lo-Fert than the Hi-Fert group. We also observed other modest associations between genomic merit for fertility with the follicular dynamics and estrous behavior. We found several associations between milk yield and parity with ovarian, endocrine, and estrous behavior phenotypes as cows with greater milk yield and in the second lactation were more likely to have unfavorable phenotypes. These results demonstrate that differences in reproductive performance between cows of different genomic merit for fertility classified based on gDPR may be partially associated with circulating concentrations of P4, the incidence of atypical phenotypes during the estrous cycles, and, to a lesser extent, the follicular wave dynamics. The observed physiological and endocrine phenotypes might help explain part of the differences in reproductive performance between cows of superior and inferior genomic merit for fertility.

Endocrine and metabolic differences between Bos taurus and Bos indicus cows and implications for reproductive management

Based on the considerable differences in ovarian morphology and function, as well as circulating hormones and metabolites between Bos indicus (B. indicus) and Bos taurus (B. taurus), researchers are using this acquired knowledge to optimize protocols for fixed-time artificial insemination (FTAI), and production of in vivo derived embryos by multiple ovulation or by in vitro embryo production (IVP). In B. indicus, at the time of follicle deviation, the dominant follicle is smaller and acquires ovulatory capacity at a smaller diameter than B. taurus. Moreover, despite ovulating smaller follicles and having smaller corpora lutea (CL), circulating concentrations of estradiol (E2) and progesterone (P4) are greater in B. indicus than B. taurus. These physiological differences may be related to greater circulating cholesterol, insulin and IGF1 in B. indicus than in B. taurus. For both genetic groups there is a negative relationship between circulating P4 and ovulatory response to the first GnRH treatment of a fixed-time AI (FTAI) protocol. Moreover, despite lower clearance rates of steroid hormones in B. indicus than B. taurus, the dose of 2 mg estradiol benzoate seems to be the most effective either for Nelore (B. indicus beef), Angus (B. taurus beef), or Holstein (B. taurus dairy) cows at the initiation of an E2/P4-based FTAI protocol to optimize synchronization and pregnancy per AI (P/AI). Several studies have shown that only one recommended dose of PGF2α at a FTAI protocol may be insufficient for adequate luteolysis in B. indicus and B. taurus. When submitted to multiple ovulation and embryo transfer, B. indicus cows and heifers need less FSH than B. taurus to achieve superovulation. Moreover, IVP has been more successful in B. indicus than B. taurus due to greater antral follicle count and anti-mullerian hormone, and better oocyte quality.

Aspects and mechanisms of low fertility in anovulatory dairy cows

Postpartum anovulation is a natural process that is observed in most mammals, including women. In lactating dairy cows, the interval from calving to first ovulation typically averages 4 to 5 weeks, but a substantial proportion of cows have not resumed estrous cyclicity by 60 days postpartum. Extended delay in resumption of first postpartum ovulation is known to exert long-lasting detrimental effects on fertility in dairy cows including the lack of spontaneous estrus and subsequent timely insemination postpartum, but when anovular cows have the estrous cycle synchronized for artificial insemination (AI), still pregnancy per AI is reduced and the risk of pregnancy loss increased. Many risk factors exist for extended postpartum anovulatory periods such as negative nutrient balance and diseases, and these risk factors are also known to depress fertility by themselves. A key feature in anovular cows when inseminated is that they develop the ovulatory follicle under subluteal or low concentrations of progesterone. Progesterone from the corpus luteum is pivotal for follicle development, oocyte competence, embryo growth, and endometrial function; however, many of these effects exerted by progesterone are mediated either by secretion of gonadotropins influencing follicular function and oocyte competence or by endometrial histotroph secretion influencing embryo/conceptus growth and developmental biology

Endocrine and metabolic differences between Bos taurus and Bos indicus cows and implications for reproductive management

Based on the considerable differences in ovarian morphology and function, as well as circulating hormones and metabolites between Bos indicus (B. indicus) and Bos taurus (B. taurus), researchers are using this acquired knowledge to optimize protocols for fixed-time artificial insemination (FTAI), and production of in vivo derived embryos by multiple ovulation or by in vitro embryo production (IVP). In B. indicus, at the time of follicle deviation, the dominant follicle is smaller and acquires ovulatory capacity at a smaller diameter than B. taurus. Moreover, despite ovulating smaller follicles and having smaller corpora lutea (CL), circulating concentrations of estradiol (E2) and progesterone (P4) are greater in B. indicus than B. taurus. These physiological differences may be related to greater circulating cholesterol, insulin and IGF1 in B. indicus than in B. taurus. For both genetic groups there is a negative relationship between circulating P4 and ovulatory response to the first GnRH treatment of a fixed-time AI (FTAI) protocol. Moreover, despite lower clearance rates of steroid hormones in B. indicus than B. taurus, the dose of 2 mg estradiol benzoate seems to be the most effective either for Nelore (B. indicus beef), Angus (B. taurus beef), or Holstein (B. taurus dairy) cows at the initiation of an E2/P4-based FTAI protocol to optimize synchronization and pregnancy per AI (P/AI). Several studies have shown that only one recommended dose of PGF2α at a FTAI protocol may be insufficient for adequate luteolysis in B. indicus and B. taurus. When submitted to multiple ovulation and embryo transfer, B. indicus cows and heifers need less FSH than B. taurus to achieve superovulation. Moreover, IVP has been more successful in B. indicus than B. taurus due to greater antral follicle count and anti-mullerian hormone, and better oocyte quality.(AU)

Aspects and mechanisms of low fertility in anovulatory dairy cows

Postpartum anovulation is a natural process that is observed in most mammals, including women. In lactating dairy cows, the interval from calving to first ovulation typically averages 4 to 5 weeks, but a substantial proportion of cows have not resumed estrous cyclicity by 60 days postpartum. Extended delay in resumption of first postpartum ovulation is known to exert long-lasting detrimental effects on fertility in dairy cows including the lack of spontaneous estrus and subsequent timely insemination postpartum, but when anovular cows have the estrous cycle synchronized for artificial insemination (AI), still pregnancy per AI is reduced and the risk of pregnancy loss increased. Many risk factors exist for extended postpartum anovulatory periods such as negative nutrient balance and diseases, and these risk factors are also known to depress fertility by themselves. A key feature in anovular cows when inseminated is that they develop the ovulatory follicle under subluteal or low concentrations of progesterone. Progesterone from the corpus luteum is pivotal for follicle development, oocyte competence, embryo growth, and endometrial function; however, many of these effects exerted by progesterone are mediated either by secretion of gonadotropins influencing follicular function and oocyte competence or by endometrial histotroph secretion influencing embryo/conceptus growth and developmental biology…(AU)

Maintenance or regression of the corpus luteum during multiple decisive periods of bovine pregnancy

In ruminants, there are specific times during the estrous cycle or pregnancy when the corpus luteum (CL) may undergo regression. This review has attempted to summarize the physiological and cellular mechanisms involved in CL regression or maintenance during four distinct periods. The first period is near day 7 when animals that are ovulating after a period of low circulating progesterone (P4), such as first pubertal ovulation or first postpartum ovulation, are at risk of having a premature increase in Prostaglandin F2α (PGF) secreted from the uterus resulting in early CL regression and a short estrous cycle. The second period is when normal luteolysis occurs at day 18-25 of the cycle or when the CL is rescued by interferon-tau secreted by the elongating embryo. The uterine mechanisms that determine the timing of this luteolysis or the prevention of luteolysis have been generally defined. Induction and activation of endometrial E2 receptors result in induction of endometrial oxytocin receptors that can now be activated by normal pulses of oxytocin. Of particular importance is the observation that the primary mechanisms are only activated through local (ipsilateral) and not a systemic route due to transfer of PGF from the uterine vein to the ovarian artery. In addition at the CL level, studies are providing definition to the cellular and molecular mechanisms that are activated in response to uterine PGF pulses or pregnancy

Maintenance or regression of the corpus luteum during multiple decisive periods of bovine pregnancy

In ruminants, there are specific times during the estrous cycle or pregnancy when the corpus luteum (CL) may undergo regression. This review has attempted to summarize the physiological and cellular mechanisms involved in CL regression or maintenance during four distinct periods. The first period is near day 7 when animals that are ovulating after a period of low circulating progesterone (P4), such as first pubertal ovulation or first postpartum ovulation, are at risk of having a premature increase in Prostaglandin F2α (PGF) secreted from the uterus resulting in early CL regression and a short estrous cycle. The second period is when normal luteolysis occurs at day 18-25 of the cycle or when the CL is rescued by interferon-tau secreted by the elongating embryo. The uterine mechanisms that determine the timing of this luteolysis or the prevention of luteolysis have been generally defined. Induction and activation of endometrial E2 receptors result in induction of endometrial oxytocin receptors that can now be activated by normal pulses of oxytocin. Of particular importance is the observation that the primary mechanisms are only activated through local (ipsilateral) and not a systemic route due to transfer of PGF from the uterine vein to the ovarian artery. In addition at the CL level, studies are providing definition to the cellular and molecular mechanisms that are activated in response to uterine PGF pulses or pregnancy…(AU)

Effect of uterine environment on embryo production and fertility in cows

Oocyte fertilization rates in bovines following artificial insemination or natural mating are generally good (~90%). Curiously, only about one third of these pregnancies remain until 30 days post-AI in dairy cows. Thus, most pregnancies are lost between fertilization and early embryonic growth. Although classical pathways describing that lower progesterone post-AI is the main culprit to these early embryonic losses, a number of environmental factors such as heat-stress as well as novel concepts in bovine physiology including the effects of excessive negative energy balanced (NEB) and the insulin-resistant state experienced by high producing cows during the postpartum period can help explain the poor reproductive performance, generally observed in dairy herds world-wide. Thus, expanding the scientific knowledge in these critical areas in bovine fertility related to the evident impact of NEB and/or altered circulating and uterine metabolites in the postpartum period on oocyte quality; gamete transport, uterine environment, and early embryonic growth are of major importance to improve reproductive efficiency in modern high producing dairy cows.

Effect of uterine environment on embryo production and fertility in cows

Oocyte fertilization rates in bovines following artificial insemination or natural mating are generally good (~90%). Curiously, only about one third of these pregnancies remain until 30 days post-AI in dairy cows. Thus, most pregnancies are lost between fertilization and early embryonic growth. Although classical pathways describing that lower progesterone post-AI is the main culprit to these early embryonic losses, a number of environmental factors such as heat-stress as well as novel concepts in bovine physiology including the effects of excessive negative energy balanced (NEB) and the insulin-resistant state experienced by high producing cows during the postpartum period can help explain the poor reproductive performance, generally observed in dairy herds world-wide. Thus, expanding the scientific knowledge in these critical areas in bovine fertility related to the evident impact of NEB and/or altered circulating and uterine metabolites in the postpartum period on oocyte quality; gamete transport, uterine environment, and early embryonic growth are of major importance to improve reproductive efficiency in modern high producing dairy cows. (AU)

The physiology and impact on fertility of the period of proestrus in lactating dairy cows

In cattle, proestrus begins with the initiation of luteolysis and ends with initiation of estrus and the GnRH/LH surge. This period is marked by a dramatic decrease in circulating progesterone (P4 ) that reaches a nadir by about 36-48 h in cows undergoing natural or prostaglandin F2α (PGF )-induced luteolysis. Inadequate luteolysis is a cause of reduced fertility particularly in timed AI programs with small elevations in circulating P4 reducing fertility. Increasing circulating estradiol ( E2 ) during proestrus is dependent on presence, size, and function of the dominant follicle and this varies during natural proestrus, due to whether animals have two or three follicular waves, and during PGF-induced proestrus, according to stage of the follicular wave at time of PGF treatment. Inadequate circulating E2 can limit fertility and increase pregnancy loss in some specific circumstances such as in cows with low BCS and in cows during heat stress. Thus, studies to optimize the length of proestrus and the concentrations of E2 and P4 during proestrus could produce substantial improvements in fertility and reductions in pregnancy loss.

The physiology and impact on fertility of the period of proestrus in lactating dairy cows

In cattle, proestrus begins with the initiation of luteolysis and ends with initiation of estrus and the GnRH/LH surge. This period is marked by a dramatic decrease in circulating progesterone (P4 ) that reaches a nadir by about 36-48 h in cows undergoing natural or prostaglandin F2α (PGF )-induced luteolysis. Inadequate luteolysis is a cause of reduced fertility particularly in timed AI programs with small elevations in circulating P4 reducing fertility. Increasing circulating estradiol ( E2 ) during proestrus is dependent on presence, size, and function of the dominant follicle and this varies during natural proestrus, due to whether animals have two or three follicular waves, and during PGF-induced proestrus, according to stage of the follicular wave at time of PGF treatment. Inadequate circulating E2 can limit fertility and increase pregnancy loss in some specific circumstances such as in cows with low BCS and in cows during heat stress. Thus, studies to optimize the length of proestrus and the concentrations of E2 and P4 during proestrus could produce substantial improvements in fertility and reductions in pregnancy loss.(AU)

Effects of energy and protein nutritionin the dam on embryonic development

This review highlights the importance of energy and protein nutrition of the dam on embryo production and embryo development. Fertility is reduced by greater negative energy balance post-partum as manifest by reductions in fertility and embryo quality associated with lower body condition score (BCS) but particularly with greater postpartum loss of BCS. In addition, excessive energy intake, particularly from high carbohydrate diets can reduce fertilization and embryo quality in some but not all circumstances. High protein diet s have been found to reduce embryo quality by day 7 after breeding, possibly due to greater blood urea nitrogen, however this negative effect is not observed in all studies. Sufficient circulating concentrations of amino acids, particularly rate-limiting amino acids such as methionine and lysine are critical for optimal milk production. The rate-limiting amino acids may also impact embryonic development, perhaps through improved amino acid profiles in the uterine lumen. Methionine may also have direct epigenetic effects in the embryo by methylation of DNA. Future studies are needed to replicate previously observed positive and negative effects of energy, excess protein, and amino acid supplementation in order to provide further insight into how embryonic development can be rationally manipulated using nutritional strategies.

Effects of energy and protein nutritionin the dam on embryonic development

This review highlights the importance of energy and protein nutrition of the dam on embryo production and embryo development. Fertility is reduced by greater negative energy balance post-partum as manifest by reductions in fertility and embryo quality associated with lower body condition score (BCS) but particularly with greater postpartum loss of BCS. In addition, excessive energy intake, particularly from high carbohydrate diets can reduce fertilization and embryo quality in some but not all circumstances. High protein diet s have been found to reduce embryo quality by day 7 after breeding, possibly due to greater blood urea nitrogen, however this negative effect is not observed in all studies. Sufficient circulating concentrations of amino acids, particularly rate-limiting amino acids such as methionine and lysine are critical for optimal milk production. The rate-limiting amino acids may also impact embryonic development, perhaps through improved amino acid profiles in the uterine lumen. Methionine may also have direct epigenetic effects in the embryo by methylation of DNA. Future studies are needed to replicate previously observed positive and negative effects of energy, excess protein, and amino acid supplementation in order to provide further insight into how embryonic development can be rationally manipulated using nutritional strategies.(AU)

Relationships between growth of the preovulatory follicle and gestation success in lactating dairy cow

This report summartizes three studies conducted with lactating dairy cws aiming to increase pregnancy rates to fixes time artificial insemination (TAI) protocols. Experiment I was designed to determine if changing the the timing of PGF2α treatment during an E2/P4 based program would affect fertility to TAI or fixedtime embryo transfer (TET). In experiment 2, pregnancy rates to AI were compared following synchronized ovulation using two protocols that have been developed to reduce the period between follicular wave emergence and TAI. The Ovsynch type protocol utilizes GnRH to synchronize the follicular wave by inducing ovulati on of a dominant follicle at the beginning of the protocol, and to synchronize ovulation at the end of the protocol allowing TAI. In contrast, E2/P4 based protocols utilize E2 products in the presence of P4 to induce atresia of antral follicles and synchro nize emergence of a new follicular wave. At the end of E2/P4 based protocol another E2 treatment in the absence of P4 is used to induce LH release and synchronize ovulation and allow TAI. Experiment 3 was designed to determine whether increasing the length time interval with reduced circulating P4 (proestrus) would increase fertility in a TAI program that utilized E2 and P4 to synchronize ovulation of cycling, lactating dairy cows. The overall conclusions are that circulating concentrations of progesterone and estradiol prior to and circulating concentrations of progesterone following ovulation can affect fertility in cattle. In addition, small increases in P4 concentrations near the time of AI, due to lack of complete CL regression, result in reductions in fertility. Earlier treatment with PGF2α should allow greater time for CL regression, an increase in estradiol and subsequent reductions in circulating P4 that could be critical for fertility. Optimization of follicle size in TAI programs is clearly an intr icate balance between oocyte quality, adequate circulating E2 near AI, and adequate circulating P4 after AI.

Relationships between growth of the preovulatory follicle and gestation success in lactating dairy cow

This report summartizes three studies conducted with lactating dairy cws aiming to increase pregnancy rates to fixes time artificial insemination (TAI) protocols. Experiment I was designed to determine if changing the the timing of PGF2α treatment during an E2/P4 based program would affect fertility to TAI or fixedtime embryo transfer (TET). In experiment 2, pregnancy rates to AI were compared following synchronized ovulation using two protocols that have been developed to reduce the period between follicular wave emergence and TAI. The Ovsynch type protocol utilizes GnRH to synchronize the follicular wave by inducing ovulati on of a dominant follicle at the beginning of the protocol, and to synchronize ovulation at the end of the protocol allowing TAI. In contrast, E2/P4 based protocols utilize E2 products in the presence of P4 to induce atresia of antral follicles and synchro nize emergence of a new follicular wave. At the end of E2/P4 based protocol another E2 treatment in the absence of P4 is used to induce LH release and synchronize ovulation and allow TAI. Experiment 3 was designed to determine whether increasing the length time interval with reduced circulating P4 (proestrus) would increase fertility in a TAI program that utilized E2 and P4 to synchronize ovulation of cycling, lactating dairy cows. The overall conclusions are that circulating concentrations of progesterone and estradiol prior to and circulating concentrations of progesterone following ovulation can affect fertility in cattle. In addition, small increases in P4 concentrations near the time of AI, due to lack of complete CL regression, result in reductions in fertility. Earlier treatment with PGF2α should allow greater time for CL regression, an increase in estradiol and subsequent reductions in circulating P4 that could be critical for fertility. Optimization of follicle size in TAI programs is clearly an intr icate balance between oocyte quality, adequate circulating E2 near AI, and adequate circulating P4 after AI.(AU)

Positive and negative effects of proges terone during timed AI protocols in lactating dairy cattle

Circulating concentration of progesterone (P4) is determined by a balance between P4 production, primarily by corpus luteum (CL), and P4 metabolism, primarily by liver. The volume of large luteal cells in the CL is a primary factor regulating P4 production. Rate of P4 metabolism is generally determined by liver blood flow and can be of critical importance in determining circulating P4 concentrations, particularly in dairy cattle. During timed AI protocols, elevations in P4 are achieved by increasing number of CL by ovulation of accessory CL or by supplementation with exogenous P4. Dietary manipulations, such as fat supplementation, can also be used to alter circulating P4. Elevating P4 prior to the timed AI generally decreases double ovulation an d can increase fertility to the timed AI. This appears to be an effect of P4 during the follicular wave that produces the future ovulatory follicle, possibly by altering the oocyte and subsequent embryo. Near the time of AI, slight elevations in circulating P4 can dramatically reduce fertility. The etiology of slight elevations in P4 near AI is inadequate luteolysis to the prostaglandin F2 α (PGF) treatment prior to timed AI. After AI, circulating P4 is critical for embryo growth and establishment and maintenance of pregnancy. Many studies have attempted to improve fertility by elevating P4 after timed AI. Combining results of these studies indicated only marginal fertility benefits of <5%. In conclusion, previous research has provided substantial insight into the effects of supplemental P4 on fertility and there is increasing insight into the mechanisms regulating circulating P4 concentrations and actions. Understanding this prior research can focus future re search on P4 manipulation to improve timed AI protocols.

Positive and negative effects of proges terone during timed AI protocols in lactating dairy cattle

Circulating concentration of progesterone (P4) is determined by a balance between P4 production, primarily by corpus luteum (CL), and P4 metabolism, primarily by liver. The volume of large luteal cells in the CL is a primary factor regulating P4 production. Rate of P4 metabolism is generally determined by liver blood flow and can be of critical importance in determining circulating P4 concentrations, particularly in dairy cattle. During timed AI protocols, elevations in P4 are achieved by increasing number of CL by ovulation of accessory CL or by supplementation with exogenous P4. Dietary manipulations, such as fat supplementation, can also be used to alter circulating P4. Elevating P4 prior to the timed AI generally decreases double ovulation an d can increase fertility to the timed AI. This appears to be an effect of P4 during the follicular wave that produces the future ovulatory follicle, possibly by altering the oocyte and subsequent embryo. Near the time of AI, slight elevations in circulating P4 can dramatically reduce fertility. The etiology of slight elevations in P4 near AI is inadequate luteolysis to the prostaglandin F2 α (PGF) treatment prior to timed AI. After AI, circulating P4 is critical for embryo growth and establishment and maintenance of pregnancy. Many studies have attempted to improve fertility by elevating P4 after timed AI. Combining results of these studies indicated only marginal fertility benefits of <5%. In conclusion, previous research has provided substantial insight into the effects of supplemental P4 on fertility and there is increasing insight into the mechanisms regulating circulating P4 concentrations and actions. Understanding this prior research can focus future re search on P4 manipulation to improve timed AI protocols.(AU)