Anovulatory Cycles

Take Home Message: In the mare, the prediction of an ovulatory follicles is often challenging. Although their etiology remains largely unknown, appropriate management of mares predisposed to anovulatory cycles may decrease their incidence.

I. INTRODUCTION

Anovulatory cycles in the mare represent a source of substantial reproductive inefficiency and economic loss to the equine breeding industry. These nonproductive cycles are enormously frustrating to both breeders and veterinarians. Not only are time and mare management costs lost when a mare fails to ovulate, but valuable semen and the expense associated with its attainment, processing and handling may also be incurred as well. Thus, prediction, prevention and treatment for an ovulatory cycles would be of great benefit to the horse breeding industry.

II. PREDISPOSITION

Anovulatory follicles are commonly encountered in mares that are undergoing transitional cycles in both the spring and fall,¹ at which time they are considered to be a normal physiological event. Additionally, the development of anovulatory follicles may occur occasionally during the breeding season, but are more commonly seen in older mares. The author has also found anovulatory cycles to be common in mares with pituitary dysfunction as well as in mares that are in high levels of competition. Overall, the incidence of an ovulatory cycles has been reported to range between 5-25%.^1,2 Anovulatory follicles appear to be unresponsive to available ovulation induction agents, and their persistence may increase the interestrous interval.¹ It is interesting to note that, in a given breeding season, affected mares tend to have repeated a novulatory cycles.³

III. DIAGNOSIS

The ultrasonographic appearance of anovulatory follicles suggests that they have different forms and perhaps develop from different etiologies. Anovulatory follicles may appear as hemorrhagic anovulatory follicles (HAFs), wherein the antrum of the preovulatory follicle fills with blood and fails to reorganize appropriately. Hyperechoic flecks of fibrin or webs of fibrin strands often become visible as the follicle remodels. In these anovulatory follicles, the follicular wall also appears hyperechoic on ultrasound examination, as it luteinizes and is capable of progestin secretion. Especially in mid-late diestrus (8-14 days post formation), this type of HAF may ultimately undergo luteolysis in reponse to prostaglandin (PG) administration, or serial PG injections over several days, or it may regress spontaneously, but an increased interestrous interval is not un common. Interestingly, the use of PG analogues early in diestrus has also be enreported to be associated with development of this type of HAF,^4,5 possibly due to a premature in crease in LH levels during a follicular wave.⁶

Anovulatory follicles may also appear as cyst-like preovulatory follicles th at g row to disproportionate size an d p ersist for subsequent estrous cycles, hence termed persistent anovulatory follicles (PAF). Lastly, similar to developments occurring during the vernal transition period, dominant a novulatory follicles may simply regress instead of proceeding to ovulation.

Endocrine profiles, ovarian and follicular blood flow, as well as the expression of ovarian angiogenic fact ors have been examined to determine their potential relationship, if any, with anovulatory cycles. Ginther et al⁷ examined progestrone, estradiol, luteinizing hormone and follicle stimulating hormone and reported that the only difference bet ween mares with ovulatory v ersus a novulatory cycles, was an elevation in estradiol levels 3 days prior to ovulation in anovulatory cycles when compared to ovulatory cycles. Examining additional periovulatory hormones associated with ovulation regulation, Metcalf and Roser⁸ concluded that neither periovulatory prolactin nor cortisol concentrations were found to be significantly different between mares with normal ovulations and those with anovulatory cycles.

Ovarian and follicular blood flow of ovulatory and non ovulatory follicles has also been compared. Ginther et al⁷ found that the follicular wall of anovulatory follicles demonstrated a lesser degree of vascularization 1 day prior to predicted ovulation in comparison to follicles undergoing successful ovulation. In another study, ovarian cell populations were examined with immunohistochemistry for expression of vascular endothelial factors. The researchers concluded that, despite the apparent expression of sufficient VEGF-A in the AHFs to allow ovulation and corpus luteum formation, there was a lack of the receptor, Fl k-1, which affects the pro-angiogenic activity of VEGF-A, which could be a reason for ovulation failure associated with HAF formation.⁹

Researchers have also compared follicular fluid components of equine ovulatory follicles during the physiological breeding season to anovulatory follicles in seasonally anestrous mares in attempt to further understand the mechanisms involved in anovulation. Don adeau and Watson¹⁰ reported re duced follicular fluid levels of progestins, testosterone and IGF-1 in anestrous follicles in comparison to estrous follicles, which are likely a result of reduced gonadotropin stimulation at that time of year. In a more recent study, Donadeau and Schauer¹¹ further disclosed t hat microRNA expression differed significantly between follicular fluid obtained during the ovulatory and anovulatory seasons; although the significance of this finding is not yet understood, the results may be used to further elucidate the mechanisms involved in follicle maturation and ovulation.

IV. PREVENTION

To date, there are no proven treatments for the prevention of anovulatory cycles. However, one may perhaps lessen the chance of their occurrence in mares with a history of an ovulation by:

1. Avoid breeding during seasonal transition periods.
2. Limit the use of PG in early diestrus.
3. Limit the use of drugs that inhibit secretion of PG in the periovulatory period.
4. Treat underlying metabolic and endocrine disease.
5. Track follicular perfusion of the dominant follicle in the periovulatory period.
6. Consider the use of d mperidone, a dopamine antagonist, during estrus.

V. CONCLUSION

Despite the results of the studies presented, the exact cause of anovulatory follicles is still unknown and reliable prediction remains elusive. Furthermore, not only do the underlying follicular processes that generate maturation of the follicle differ between ovulatory and anovulatory follicles, the mechanisms that generate different forms of anovulatory follicles may not be the same. An interesting area of research may lie with a potent GnRH secretagogue, kisspeptin, and its effect on follicle maturation, although current research does not support its direct effect in ovulation induction.¹²

VI. REFERENCES

1. McCue PM, Squires E.L. Persistent an ovulatory follicles in the mare. Theriogenology 2002;58:541-543.
2. Cuervo-Arango J , Newcombe JR. Risk factors f or t he development of haemorrhagic anovulatory follicles in the mare. Reprod Domest Anim 2010;45(3):473-80.
3. Cuervo-Arango J , Newcombe JR . The effect of cloprostenol on the incidence of multiple ovulation and anovulatory hemorrhagic follicles in two mares: a case report. J Equine Vet Sci 2009a;29(6):533-539.
4. Cuervo-Arango J, Newcombe JR. The effect of hormone treatments (hCG and cloprostenol) and season on the incidence of hemorrhagic an ovulatory follicles in the mare: a field study. Theriogenology 2009b;72(9):26-127.
5. Schauer SN, Guillaume D, Decourt C, et al. Effect of luteinizing hormone overstimulation on equine follicle maturation. Theriogenology 2013;79:409-416.
6. Ginther OJ , Gastal MO, Gastal EL, et al. Induction of haemorrhagic anovulatory follicles in mares. Reprod Fertil Dev 2008;20(8):947-954.
7. Ginther OJ, Gastal MO, Ga stal EL, et al. Incidence, endocrinology, vascularity, and morphology of hemorrhagic anovulatory follicles in mares. J Equine Vet Sci 2007;27(3):130-139.
8. Metcalf ES, Roser JF. The relationships between prolactin and cortisol levels and t he f ormation of an ovulatory follicles in the mare. Anim Reprod Sci 2010;121s:54.
9. Ellenberger C , Müller K, Schoon HA, et al. Histological and immunohistochemical characterization of equine anovulatory haemorrhagic follicles (AHFs). Reprod Domest Anim 2009;44(3):395-405.
10. Donadeu FX , Watson ED. Seasonal Changes in ovarian activity: lessons learnt from the horse. Anim Reprod Sci 2007;100:225-242.
11. 11. Donadeu FX, Schauer SN. Differential miRNA expression between equine ovulatory and anovulatory follicles. Dom Anim Endocrinol 2013;45(3):122-125.
12. Decourt C, Caraty A, Br iant C. Acute injection and chronic perfusion of kisspeptin elicit gonadotropins release but fail to trigger ovulation in the mare. Biol Reprod 2014;90(2):36.