Endocrinology of the Late Gestational Mare in Health and Disease
ACVIM 2008
Michelle M. LeBlanc, DVM, DACT
Lexington, KY, USA

Introduction

Hormones involved in equine pregnancy may be broadly divided into three groups, on the basis of their physiological function. First are those hormones that regulate myometrial quiescence and ensure that the uterus does not expel the fetus until it is mature and ready for birth. Second are those hormones which stimulate uterine activity and cause regular, rhythmic myometrial contractions resulting in rapid delivery of the foal and placenta. Third are those hormones that induce fetal maturation. Delivery of a viable foal at term depends on the coordination of these endocrine events to ensure that there is synchronization between fetal development, fetal maturation and maternal readiness for birth. Late gestation abortions and pre-term deliveries occur when these endocrine processes are disrupted by infectious agents or pathological changes to the feto-placental unit or by maternal disease.

Hormones Associated with Myometrial Quiescence

Progestins (Progesterone [P4] and Its Metabolites)

In most mammalian species, P4 is the dominant progestin during pregnancy with levels slowly declining to zero by parturition. The mare differs from other species in that total progestins rise in the last three weeks of pregnancy while maternal plasma P4 concentrations are negligible from mid-gestation to parturition. The ovary is the source of progesterone in the mare until day 120-150 of gestation; after that time, progesterone is synthesized by the feto-placental unit from the precursor pregnenolone (P5) derived from the fetal adrenal. The P5 is converted into P4 in the placenta and then into 5 α-pregnane, 3,20,-dione (DHP) in the endometrium. Most 5 α-DHP is then returned to the fetus and further metabolized into other progestins, while some (30%) is excreted into the maternal circulation along with other progestins. Most P4 remains within the uteroplacental tissues, where it can presumably direct steroid metabolism and regulate myometrial activity. Total progestin concentrations in maternal plasma are low until 15-21 days before parturition when levels rise dramatically, only to fall precipitously 24 hours before foaling. The pre-partum rise in progestins is associated with development of the mammary gland and onset of mammary secretion electrolyte changes, whereas the decline is concurrent with an increase in fetal cortisol. Because progestins cross react with the progesterone antibody used in commercial radioimmunoassay and enzyme-linked immunosorbent assays, progestin concentrations can be measured in the maternal circulation in late gestation. Values may vary between laboratories because of the different levels of cross-reactivity between assays, however, concentrations should remain constant with levels ranging from 2 to 12 ng/ml until the last three weeks of gestation.

Relaxin

Relaxin is produced by placental trophoblast cells. Maternal concentrations are high in late gestation and increase again during labor. Substantial differences in relaxin levels have been observed between breeds. Preliminary evidence indicates that relaxin concentrations decline before abortion. Relaxin may be useful as a biological marker of placental viability provided that suitable equine assays become available.

Uterotonic Hormones

Estrogens

The term feto-placental unit derives from the discovery in the 1960s that the placenta and the fetus in human pregnancies each lack a complete system of enzymes for the biosynthesis of estrogens. Only when their activities are combined are estrogens synthesized. The fetal component in humans is the adrenal gland while, in the horse, the fetal gonads provide the precursors for estrogen formation by the placenta. Circulating concentrations of maternal estrogens parallel the increase and decrease in size of the fetal gonads between 150 and 280 days of gestation. Peak total estrogen concentrations occur around 210 days of gestation. Two types of estrogens are synthesized from precursors produced by the fetal gonads, estrone, estradiol-17α and β and the equine-unique ring B unsaturated estrogens, equilin and equilenin. These estrogens are not essential for pregnancy maintenance, as removal of the fetal gonads does not affect the length of gestation in the mare. However, labor is prolonged, maternal plasma prostaglandin F concentrations are low during labor and the fetuses are growth retarded suggesting that estrogens may affect uterine contractility and blood flow in the horse. In other species, the pre-partum rise in estrogens promotes synthesis of prostaglandins, increases in oxytocin receptors and myometrial gap junctions, and mediates a switch from low amplitude, irregular myometrial contractures to high amplitude, regular contractions of labor. A similar pattern is emerging in pregnant mares whereby uterine electromyographic activity is elevated during the final week pre-partum, particularly at night, and is correlated with nocturnal increases in plasma estradiol 17β concentrations.

Prostaglandins (PG)

Prostaglandins are involved in labor and if administered after mid-gestation, parturition will be induced. PGFpromotes myometrial contractility whereas PGE2 promotes cervical relaxation. Both are synthesized by utero-placental tissues and are present in maternal and fetal plasma and allantoic fluid. It is difficult to measure these hormones accurately as they are labile so the more stable metabolite PGFM is measured in peripheral plasma. PGs are rapidly metabolized into inactive metabolites by the enzyme 15-hydroxyprostaglandin dehydrogenase (PGDH) which is present in the endometrium from approximately 150 days of gestation. Progesterone may act in a paracrine fashion to regulate PGDH. The increase in progestins in late gestation inhibits enzymes that result in a decline in P4 synthesis, thus decreasing PGDH activity and enabling an increase in PG concentrations and onset of myometrial contractions.

Oxytocin (OX)

OX is a peptide hormone secreted by the posterior pituitary gland. Plasma OX concentrations are low in pregnant mares throughout gestation and only increase during labor. It has been suggested that OX may act in a paracrine manner within the utero-placental tissues and that high oxytocin receptors are more important than high circulating OX concentrations. Although uterine OX receptors have not been quantified in the pregnant mare, it is likely that they are present in high concentrations because of the marked sensitivity of the mare's uterus to low doses of OX.

Hormones Associated with Maturation-Cortisol

An increase in fetal cortisol before delivery is essential for maturation of fetal organ systems and for the initiation of parturition. In the horse, a marked rise in fetal cortisol occurs only within the last 2 to 3 days of gestation and this coincides with the decline in total progestins concentrations in maternal plasma, a change in the fetal neutrophil:lymphocyte ratio from 1:1 to 4:1 and a dramatic rise in fetal thyroid hormones. This switch from progestins to cortisol production is achieved via induction 17 α-hydroxylase, the adrenal enzyme that is needed to convert P4 to cortisol. The rise in fetal cortisol is stimulated by increases in fetal plasma corticotropin (ACTH) concentrations, enhanced sensitivity of the adrenal cortex to ACTH and a decrease in the cortisol-binding capacity over the last weeks of gestation. Because cortisol is essential for fetal maturation, foals delivered before the rise in fetal cortisol exhibit typical signs of prematurity and may die from multi-organ failure.

Endocrine Changes Associated with Feto-placental Problems

Clinical conditions that affect the placenta or fetus are likely to disrupt the endocrine capacity of the feto-placental unit. Maternal signs are manifested only after the disease process alters endocrine pathways and stimulates inflammatory and immune responses. Consequently, hormone patterns in maternal plasma often reflect later rather than early stages of a disease. Feto-placental function can be monitored by measuring total progestins in three or more samples of maternal plasma obtained at 48 to 72 h intervals. Three abnormal progestin patterns have been observed, a premature, rapid decline, a precocious increase or a failure to exhibit the normal prepartum rise. A rapid decline in progestins is most frequently seen in acute conditions where there is fetal death or imminent fetal expulsion. A precocious rise in progestins is usually associated with placental pathology. A failure to rise in the last 3 weeks of gestation is almost exclusively found in mares exposed to ergopeptine alkaloids from the endophyte fungus found on tall fescue grass (fescue toxicosis). In general, mares with precociously high progestin concentrations are more likely to deliver live foals than those with low concentrations because there has been some degree of fetal hypothalamo-pituitary-adrenal activity.

Measurement of a single plasma sample of total estrogens also has been advocated as an indicator of fetal well being. A total estrogen concentration > 1000 ng/ml between 150 and 280 days of gestation is considered to be normal while concentrations < 500 ng/ml have been associated with a severely compromised or dead fetusand levels between 500-800 ng/ml indicate a compromised fetus. It is doubtful that total estrogen concentration can predict fetal death as the fetal gonads are unlikely to respond to fetal stress. Other hormones such as PGFand PGE2 in allantoic fluid and fetal cortisol have been shown to increase in mares with experimentally induced placentitis or after fetal catheterization, however, it is unlikely that they can be used diagnostically because they are either rapidly metabolized (PGFand PGE2) and their release may be localized within the uterus or fetus (fetal cortisol).

References

1.  Ginther OJ. Reproductive Biology of the Mare 1992; 392;

2.  Holton DW, et al. J Reprod Fert 1991; Suppl 44: 517;

3.  Chavatte PM, et al. Equine Vet J 1997; Suppl 24:89;

4.  Ousey JC, et al. Biol of Reprod 2003; 69:540;

5.  Hamon M, et al. J Reprod Fert suppl 1991:44:529;

6.  Han X, et al. Equine Vet J 1995; 27: 334;

7.  Morris S, et al. Theriogenology 2007;67:681;

8.  Klonisch T, et al. Reprod Domest Anim 2000;35:149;

9.  Stewart DR, et al. Equine Vet J 1984: 16:270;

10. Ryan P, et al. Proceed Am Assoc Equine Pract 1998; 44:62;

11. Raeside JI. Proceedings. Workshop on the Equine Placenta 2003; 42;

12. Pashen RL, Allen WR. J Reprod Fert 1979; suppl 27: 499;

13. Silver M. Exper Physiology 1990; 75: 285;

14. McGlothlin JA, et al. Reproduction 2004;127:57;

15. O'Donnell LJ, et al. Reprod Domest Anim 2003; 38: 233;

16. Silver M, et al. J Rerod Fertil 1979; Suppl 27: 531;

17. Vivrette SL, et al. J Reprod Fert 2000; 119: 347;

18. Pashen RL. Equine Vet J 1980; 12:85;

19. Fowden AL. Reprod Fert Dev 1995; 7: 351;

20. Liggins GC. Reprod Fert Dev 1995;6:141;

21. Fowden AL, Silver M. Reprod Domest Anim 1995; 30:170;

22. Cudd TA, et al. J Endocrinology 1995; 144:271;

23. Rossdale PD, et al. J Reprod Fert 1991; Suppl 44: 579-590.

24. Ousey JC, et al. Theriogenology 2005: 63: 1844;

25. Santschi EM, et al. J Reprod Fert 1991; Suppl 44:627;

26. Brendemuehl, JP, et al. Biol Repro Monograph 1995; 1: 53;

27. LeBlanc MM, et al. Proceed. Am Assoc Equine Pract 2004;50:127;

28. LeBlanc MM, et al. Theriogenology 2002; 58: 841;

29. Stawicki RJ, et al. Theriogenology 2002; 58: 849.

Speaker Information
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Michelle LeBlanc, DVM, DACT
Gainesville, FL


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