Oxytocin and Maternal Recognition of Pregnancy

A research report from the laboratory at the Gluck Equine Research Center at the University of Kentucky noted that it is well-established that early conceptus loss (the embryo and its associated extra-embryonic membranes) is a major source of reproductive inefficiency in domestic animals. Early pregnancy in all mammals is characterized by a high fertilization rate followed by a high conceptus loss rate.

In horses, approximately 50% of all pregnancies are lost between fertilization and foaling. About 30% of this loss occurs during the first two weeks of gestation. The remainder is relatively evenly distributed over the rest of gestation. The actual loss rates on any given farm will vary with such factors as mare age and breeding stallion, as well as numerous on-farm management factors.

Before we can adequately recognize pregnancies at risk of being lost, we first must further our understanding of how the conceptus interacts with the maternal environment, particularly during the first few critical weeks of gestation.

Events that occur between approximately 11 and 15 days of gestation are of critical importance for the establishment and maintenance of a successful pregnancy in horses. The series of events, discussed below, has been termed ‘Maternal Recognition of Pregnancy.’ When the mare ovulates an oocyte, the cells in the wall of the follicle (the structure on the ovary that previously housed the oocyte), undergo a rapid series of changes and form a corpus luteum (CL). The CL begins secreting progesterone. The CL secretes progesterone for about two weeks, whether or not mating has occurred and whether or not pregnancy has occurred.

After about 14 days, the mare must ‘decide’ whether to maintain progesterone production or not in response to the biological question: ‘Is there a viable conceptus in the uterus?’ If the answer is ‘no,’ the uterus produces prostaglandin F2alpha (PGF), which ultimately causes the regression of the CL and a decline in progesterone production. The declining progesterone allows another follicle to develop, another estrous cycle to occur, and, ultimately, another opportunity to establish pregnancy.

If the answer is ‘yes’ to the pregnancy question, the conceptus produces a hormonal signal that suppresses uterine PGF production. When PGF production by the uterus is suppressed, then the CL can continue to secrete progesterone to support the growth and development of the conceptus.

If PGF is produced inappropriately during pregnancy, or if the conceptus is not able to suppress it sufficiently, then the pregnancy will be lost. Conversely, if PGF is not produced in the right amounts and the right time at the end of the estrous cycle, then the CL is maintained inappropriately and there is a delay to the next ovulation. Time is lost before the mare can be bred again.

Although we understand this general scenario, as yet we do not have a very good understanding of the specific mechanisms regulating the production of PGF (for luteal regression) or suppression of PGF (for pregnancy maintenance). In sheep and cattle, at the end of the estrous cycle, the CL produces the hormone oxytocin. Oxytocin then stimulates the uterus to produce PGF. Uterine PGF, in turn, stimulates the CL to produce more oxytocin. This ‘positive feedback’ between luteal oxytocin and uterine PGF ultimately causes the regression of the CL.

Studies in sheep have shown that if oxytocin production from the CL is blocked, then luteal regression is delayed and there is a subsequent delay in the amount of time it takes for the ewes to return to estrus. In addition, it is believed that the sheep or cow conceptus is able to uncouple the positive feedback loop between luteal oxytocin and uterine PGF in order for maternal recognition of pregnancy to occur.

The CL of the mare produces little, if any, oxytocin. The pituitary gland of the mare, like that of other animals, secretes oxytocin, and uterine PGF appears to stimulate pituitary release of oxytocin in mares. However, there is little evidence to suggest that pituitary oxytocin and uterine PGF form a positive feedback loop analogous to that of luteal oxytocin and uterine PGF in ruminants.

If oxytocin is given to mares toward the expected end of the estrous cycle, it will cause the uterus to release PGF. If the oxytocin is given at an equivalent time during pregnancy, the ability of the uterus to release PGF is blocked. It is reasonable to suspect, therefore, that oxytocin might be involved in luteal regression in cycling mares and in maternal recognition of pregnancy in pregnant mares. However, circulating levels of oxytocin are much lower in mares than in sheep and cattle. If oxytocin is involved in luteal regression in mares, but the circulating levels are much lower in mares compared to ruminants, it seems reasonable to look for a source of oxytocin close to the uterus. For example, if the uterus itself is producing oxytocin, then it could act directly on uterine PGF without having to gain access to the systemic circulation.

From studies begun in 1992, researchers at the Gluck Center have been able to measure synthesis of both oxytocin protein (the biologically active molecule) and mRNA (the cellular molecules that act as a template for protein synthesis). To their knowledge, that was the first evidence that the equine uterine endometrium produces oxytocin (Behrendt, C.Y.; Adams, M.H.; Daniel, K.S.; McDowell, K.J. Oxytocin expression by equine endometrium. Biol Reprod 1997; 56 Suppl 1:134).

During the breeding season of 1996, endometrial biopsies were collected from mares in estrus, at Days 5, 10, and 15 of a non-bred cycle, and at Days 10, 15, and 20 of pregnancy. The amounts of mRNA appeared to be higher at estrus and late in the cycle, around the time of expected luteal regression, than earlier in the cycle, but there was a good deal of variation among mares. During the 1997 breeding season, more samples were collected and the studies are continuing.

When researchers quantitate changes in oxytocin mRNA and protein production by the endometrium, they will be able to compare these levels to those of uterine PGF and investigate interactions between the two hormones. In this manner, researchers can gain a better understanding of luteal maintenance, luteal regression, and maternal recognition of pregnancy in mares.

The long-term goal of the research at the Gluck Center reproduction laboratory is to identify causes of pregnancy loss in horses and to develop methods of reducing the loss rates. The direct benefits to the equine industry are to increase efficiency and decrease costs of horse breeding programs.

Reprinted from Equine Disease Quarterly, Funded by Lloyd’s of London

Disclaimer: Seek the advice of a qualified veterinarian before proceeding with any diagnosis, treatment, or therapy.