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The influence of progesterone pre- and post-service

P4 plays a key role in reproductive events associated with establishment and maintenance of pregnancy

09 July 2020, at 8:10am

Fertility is one of the main drivers of herd profitability in cattle production systems through its impact on achieving greater production and maintaining short calving intervals. This is particularly true of seasonal systems with short well-defined breeding periods where calving pattern is a key driver of profitability.

Successful pregnancy establishment involves ovulation of a competent oocyte, fertilisation by a capacitated sperm and growth of the embryo in an environment conducive to normal development. While fertilisation success is typically high (greater than 85 percent) following artificial insemination (AI) in cattle, many of the resulting embryos fail to develop to term. A significant proportion of this loss occurs between fertilisation and maternal recognition of pregnancy, which in cattle occurs around day 16 post oestrus. Indeed, in high-producing dairy cows as many as 50 percent of embryos may be no longer viable by day seven (Figure 1).

FIGURE (1) Pivotal periods of pregnancy loss during the first trimester of pregnancy in lactating dairy cows (adapted from Wiltbank et al., 2016)
FIGURE (1) Pivotal periods of pregnancy loss during the first trimester of pregnancy in lactating dairy cows (adapted from Wiltbank et al., 2016)

Ruminant conceptuses undergo a characteristic elongation prior to implantation. This process is dependent on secretions from the uterus, which in turn are regulated by maternally derived P4 from the corpus luteum (CL) and conceptus-derived interferon tau (the maternal recognition factor) which induce changes in expression of genes in the uterus and impacts the composition of the uterine lumen fluid which supports growth and development of the conceptus.

Circulating concentrations of P4 in the cow represent a balance between production (by the CL) and metabolism, related to the blood flow to the liver. Various methods to elevate progesterone (P4) during growth of the preovulatory follicle have been shown to improve fertility in lactating dairy cows. Low circulating concentrations of P4 near AI, indicative of optimal CL regression, are required to optimise fertility, while elevated P4 concentrations after AI can impact embryonic development and may, in some circumstances, improve fertility. Thus, strategies to optimise P4 concentrations during selected reproductive periods may improve reproductive efficiency of lactating dairy cows.

Progesterone and the oocyte

High P4 concentrations during the growth of the ovulatory follicle are associated with improved oocyte quality and pregnancy outcomes. During the final period of follicle growth, between the preovulatory luteinising hormone (LH) surge and ovulation, the follicular fluid changes from an environment dominated by oestradiol to one that is dominated by P4 as the granulosa cells luteinise in preparation for the formation of the CL after ovulation. Given that this is coincident with resumption of meiosis and maturation of the oocyte prior to ovulation, a role in determining oocyte quality is likely. Reduced P4 concentrations during growth of the first follicular wave affects embryo quality after super-stimulation and reduces pregnancy rate in lactating dairy cows after AI; in both cases, outcomes can be improved with supplemental P4. Based on such studies, sophisticated hormonal synchronisation protocols based on Ovsynch modifications such as G6G or Double-Ovsynch have been incorporated widely into reproductive management programmes by dairy farmers, particularly in the US.

Progesterone and the endometrium

Looking at gene expression patterns in the endometrium is a useful tool to understand function. Temporal changes in endometrial gene expression occur irrespective of whether the cow is pregnant or not and it is really only at the time of maternal recognition of pregnancy at around day 16 that major changes in gene expression are detectable between pregnant and cyclic animals. In other words, the uterus is always “optimistic” and prepares for pregnancy for the first two-thirds of the cycle, even in the absence of mating. An adequate rise in P4 after ovulation is necessary to drive these normal temporal changes that occur in the endometrial transcriptome. Studies have shown that P4 supplementation advances the normal temporal changes in endometrial gene expression, in association with advanced conceptus development around day 16.

Progesterone and conceptus elongation

Elongation of the ruminant conceptus is essential for normal pregnancy recognition and implantation. The effects of elevated P4 shortly after conception on the advancement of conceptus elongation have been convincingly demonstrated in cattle and sheep. Using a combination of in vitro embryo production and in vivo embryo transfer techniques, it has been shown that the effect of P4 on conceptus development is mediated exclusively via the endometrium. Interestingly, the embryo does not need to be present in the uterus during the period of P4 elevation in order to benefit from its priming effect, strongly suggesting that the effect of P4 is via advancement of the normal temporal changes that occur in endometrial gene expression, resulting in advanced conceptus elongation.

Conceptus length on a given day in the period around pregnancy recognition is thought to be indicative of its quality and the likelihood of establishing and maintaining a pregnancy (Figure 2). There is a linear correlation between conceptus length and interferon tau production and while the threshold concentration of interferon tau to establish pregnancy is not known, it is highly likely that short (ie compromised) conceptuses do not secrete sufficient amounts for pregnancy recognition. Long and short age-matched conceptuses display different gene expression patterns related to metabolic and biosynthetic processes and immune response. Furthermore, such conceptuses elicit different responses from the endometrium which may be important for optimal maternal recognition of pregnancy.

FIGURE (2) Elongat-ing bovine conceptuses on day 14 of pregnancy. Note the large variation in conceptus length which is associated with likelihood of pregnancy establishment
FIGURE (2) Elongat-ing bovine conceptuses on day 14 of pregnancy. Note the large variation in conceptus length which is associated with likelihood of pregnancy establishment

Strategies to increase progesterone post AI

Many studies have attempted to improve fertility by elevating P4 after AI. Approaches taken to increase peripheral concentrations of P4 after AI include those that (i) increase function of the existing CL (eg strategies which promote growth of the dominant follicle before ovulation resulting in a larger CL, or luteotrophic treatments which stimulate CL development such as hCG administration; (ii) induce ovulation of a dominant follicle and formation of accessory CL (eg hCG or GnRH administration); or (iii) those which supplement progesterone directly (eg via injection or intravaginal devices). How-ever, data on outcome in terms of pregnancy rate are often conflicting or inconclusive. One issue relates to the induction of short cycles if supplemental P4 is given too early after AI (before day three or four). A recent meta-analysis concluded that P4 supplementation was beneficial only in cows of lower fertility and only after natural oestrus and that the benefits required exogenous P4 supplementation to begin between days three and seven. Thus, while a significant volume of research has provided insight into the mechanisms regulating circulating P4 concentrations and actions on the uterus and conceptus, more research is required to better understand how P4 manipulation can be repeatedly used to improve reproductive success.

Conclusion

The causes of low fertility in dairy cattle are complex and multifactorial and may be due to compromised follicle development impacting on oocyte quality, a suboptimal reproductive tract environment incapable of supporting normal embryo development or a combination of both. Progesterone plays a key role in reproductive events associated with establishment and maintenance of pregnancy through its effects on oocyte quality and its action on the uterine endometrium. Low P4 concentrations have been implicated as a causative factor in low pregnancy rates observed in high-yielding dairy cows. Elevated concentrations of P4 in the immediate post-conception period have been associated with an advancement of conceptus elongation, an increase in interferon tau production and higher pregnancy rates in cattle. Innovative strategies aimed at optimising circulating concentrations of P4 at precise times of the cycle have the potential to significantly improve embryo survival in cattle.

References
Author Year Title
Lonergan, P. 2011 Influence of progesterone on oocyte quality and embryo development in cows. Theriogenology, 76, 1594-1601
Lonergan P. and Forde N. 2015 The role of progesterone in maternal recognition of pregnancy in domestic ruminants. In: Geisert R. and Bazer F. (eds) Regulation of implantation and establishment of pregnancy in mammals. Advances in anatomy, embryology and cell biology, 216. Springer, Cham, pp 87-104
Lonergan P. and Sánchez J. M. 2020 Progesterone effects on early embryo development. Journal of Dairy Science (in press).
Spencer T. E., Forde N. and Lonergan P. 2016 The role of progesterone and conceptus-derived factors in uterine biology during early pregnancy in ruminants. Journal of Dairy Science, 99, 5941-5950
Wiltbank, M. C., Baez, G. M., Garcia-Guerra, A., Toledo, M. Z., Monteiro, P. L., Melo, L. F., Ochoa, J.C., Santos, J.E. and Sartori, R. 2016 Pivotal periods for pregnancy loss during the first trimester of gestation in lactating dairy cows. Theriogenology, 86, 239-253
Wiltbank, M. C., Souza, A. H., Carvalho, P. D., Cunha, A. P., Giordano, J. O., Fricke, P. M., Baez, G. M. and Diskin, M. G. 2014 Physiological and practical effects of progesterone on reproduction in dairy cattle. Animal, 8, Suppl 1, 70-81

Pat Lonergan, PhD, DSc, MRIA, is a Professor of animal reproduction in the School of Agriculture and Food Science at University College Dublin. His main areas of interest are early embryo development in vivo and in vitro, embryo-maternal communication and understanding embryo mortality in cattle.

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José Sánchez, DVM, MSc, PhD, a Spanish veterinarian, is currently a European College of Animal Reproduction (ECAR) resident. He is currently taking up a position at the National Institute for Agriculture and Food Research (INIA) in Madrid with a focus on embryo maternal communication.

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