Introduction

Cystic ovarian follicles (COF) have been recognized as a frequent cause of subfertility and reduced reproductive performance in cattle for over 100 years. This condition of anovulation is noted to occur in a number of mammalian species. The condition in cattle results in a major cause of economic loss worldwide, primarily to the dairy industry but its economic effects are seen in certain sectors of the beef industry as well. The major causes of economic loss involve increased days open in the postpartum period leading to extended calving intervals, drug costs associated with treatment, increased semen costs associated with the increase in servicers per conception, and higher culling rates of affected animals.^1,2 It has been shown that dairy cows with COF take 6–11 days longer to reach first service and 20–30 more days to conception than control cows.³

Terminology

Numerous terms and definitions have been used to describe the anovulatory condition of cattle, which is most commonly termed cystic ovarian disease (COD). Terms which have been used in the past to describe the same clinical condition include adrenal virilism, nymphomania, ovarian cysts, cystic ovarian degeneration, and cystic ovaries, among others.² The classic definition proposed by Roberts⁴ was the presence of an anovulatory structure on the ovary more than 2.5 cm in diameter and which has persisted for at least 10 days in the absence of a corpus luteum (CL). Several aspects of the former definitions are relatively arbitrary and do not reflect our current understanding of the condition. Cattle typically ovulate a dominant follicle with an average follicular diameter of 1.6–1.9 cm. The use of a size limit of 2.5 cm thereby excludes all cystic follicles which are smaller than this arbitrary size.⁵ Also, many previous definitions stated the requirement that the cystic structure be present for a minimum of 10 days. This requirement should also be questioned as it is now known that these structures are dynamic and can change significantly over this period and even be replaced by newer cystic structures. Additionally, current management systems would often not allow the cow to be reexamined to fulfill the 10-day duration requirement. Older definitions have also required the absence of a CL. The necessity for the absence of a CL is also not universally fulfilled as it is clearly evident that some cysts are not steroidogenic and thus are hormonally inactive and would not necessarily influence the estrous cycle. Such cystic structures can be found in the presence of a CL.

A more recent term put forth by Vanholder et al.⁵ to more accurately define and describe this anovulatory condition of cattle and its effects on reproduction is “cystic ovarian follicles.” COF is defined as the presence of a follicle(s) with a diameter of at least 20 mm, present on one or both ovaries in the absence of any active luteal tissue, and which clearly interferes with normal ovarian cyclicity.⁵

Further subclassification of the COF condition into follicular or luteal cyst is based on the degree of luteinization and on progesterone levels in blood or milk. Follicular cysts are typically thin-walled structures that secrete varying amounts of estradiol. The thickness of the layers of granulosa cells dictates the amount of estradiol present in the intrafollicular fluid. Both cyst types are considered to be different forms of the same condition, with luteal cysts being a follicular cyst in which theca and granulosa cells have undergone some luteinization and are producing progesterone.² Follicular cysts do not secrete progesterone, whereas luteal cysts secrete varying amounts of progesterone depending on the degree of luteinization. A single universal threshold level of progesterone used to distinguish follicular cysts from luteal cysts has not been consistently used among studies of this condition.⁵ Thus the ability to accurately classify each cyst as a follicular or luteal cyst remains subject to personal interpretation of the clinical examination and history in addition to ovarian ultrasound findings and serum progesterone levels.

Incidence

The incidence of COF in cattle is very dependent on their intended use and their respective management system. The incidence of COF is much greater in dairy cows compared with beef cattle and dairy heifers, where the incidence is relatively low. Utilizing data from a number of studies, the average incidence of COF in lactating dairy cattle is estimated to be near 10–12%, with various studies reporting incidences ranging from 3 to 32%.² There are numerous factors that can impact the apparent incidence of COF. The time of diagnosis can easily influence the apparent incidence of COF as it has been shown that as many as 60% of dairy cattle that develop COF recover spontaneously prior to their first postpartum ovulation and may never be diagnosed.

In beef cattle the incidence of COF is much lower when the cattle are under routine management. However, it is when the reproduction of beef cattle is intensively managed that the incidence of COF begins to rise above that of the general population. Beef cattle used for embryo donation after superovulation appear to develop COF at a much higher incidence than the general population and may approach the incidence rate of dairy cattle.

Physiology of COF formation

A dysfunction or neuroendocrine imbalance involving the normal hypothalamic–pituitary–gonadal axis resulting in ovulation failure is the basic accepted mechanism of COF formation.^1,2,6–13 However. it is the precise or primary mechanism(s) leading to ovulation failure that is the focus of extensive study. To date, the aforementioned mechanism(s) has remained elusive and is still not yet clearly identified. A complicating factor in this search is that it is clear that there are multiple factors involved in the pathogenesis, with genetic, phenotypic, environmental, cellular, and management factors all appearing to be involved in some capacity.⁵

The most widely accepted hypothesis involves the altered release of luteinizing hormone (LH) from the pituitary gland. The preovulatory surge of LH is absent, insufficient in magnitude, or improperly timed leading to failure of the dominant follicle to ovulate. The dominant follicle continues to grow and becomes large and anovulatory.^1,2,5,14 There does not appear to be a reduction in gonadotropin releasing hormone (GnRH) content in the hypothalamus or a reduction in GnRH receptors in the pituitary.⁵ LH content in the pituitary also does not appear to be reduced in cows with COF.^5,15 Injections of exogenous estradiol to cows with naturally occurring or induced follicular cysts fail to induce an LH surge, although an injection of GnRH in affected cows can induce the release of LH.^16–19 These findings support the belief that there is a functional breakdown in the positive estradiol feedback loop which controls LH secretion. Under normal conditions, preovulatory follicles secrete estrogen that has a positive feedback effect on the hypothalamic–pituitary–ovarian axis, inducing an LH surge which is responsible for ovulation of the dominant follicle.¹⁶ Because of the functional abnormality in the regulation of LH secretion, cystic cows lack an LH surge which leads to ovulation failure.

In the anovulatory condition of COF, there is also loss of the negative feedback effects of progesterone leading to relatively high levels of LH pulse secretion. These LH pulses have been observed to be higher than those in cattle with a normal luteal phase. High LH pulses promote continued and excessive growth of the dominant follicle, ultimately leading to the abnormally large preovulatory follicle.^16,20,21 Additionally, the period of estradiol and inhibin production by the dominant follicle is also protracted, which helps establish long-term dominance of the cystic follicle via suppression of follicle-stimulating hormone (FSH) production by the anterior pituitary.^16,22–25 When the COF ultimately undergoes regression and no longer produces sufficient estradiol and inhibin at levels sufficient to suppress FSH, a new follicular wave emerges. Unless the abnormality in the estradiol feedback loop is corrected, the new dominant follicle of the subsequent wave will also become cystic and anovulatory thereby sustaining or perpetuating the anovulatory condition.¹⁶ This apparent turnover and replacement of the COF condition can be responsible for the protracted anovulation noted in some cows.

There also appears to be an intraovarian component in the pathogenesis of COF. It is known that cows with follicular cysts are often concurrently or were previously exposed to various kinds of insults or stress such as oxidative stress, negative energy balance, reduced or poor liver function, and low circulating insulin-like growth factor (IGF)-1.^26–28 There has been an association with these stressors and an increase in heat shock protein (HSP) in the ovaries of cows with COF. It is speculated that the altered expression of HSP genes decreases apoptosis in the follicular wall and leads to the delayed regression of cystic follicles.²⁶ Although the precise relationship between the aberrant amounts of HSP in the ovaries of cattle under stress and the COF condition is not completely understood, it is speculated that there is an association with HSP and an intraovarian component of COF pathophysiology.²⁶

Clinical signs

The clinical sings associated with COF are generally related to altered reproductive behavior and, less frequently, changes in physical characteristics. Most commonly cows with COF show prolonged periods of anestrus, which is seen in over 80% of affected cows. This is most evident in cattle that develop COF early in the postpartum period.⁴ Nymphomania with prolonged periods of persistent and frequent estrus is seen in approximately 10% of cows with COF. It is common for the affected cow to frequently participate in riding activity of estral cows but not stand for mating herself.⁴ The presence of an extremely masculine phenotype has also been associated with cows with COF who show prolonged nymphomania.²⁹ It appears that as the interval from calving to diagnosis of COF increases, the likelihood of observing nymphomania behavior increases.⁴ Estrous cycles with sporadic and irregular patterns can also be the primary clinical sign in cattle with COF.

Diagnosis

Transrectal palpation of the reproductive tract has been the primary means of diagnosing COF for many years. However the accuracy with which one can determine the specific type of cyst present is relatively poor. However, transrectal ultrasound can be very useful in determining the specific type of cyst present. Follicular cysts typically have a thin wall (≤3 mm) whereas luteal cysts typically have a thicker and more echogenic wall (≥3 mm). The follicular fluid is often hypoechoic in follicular cysts, whereas with luteal cysts echogenic strands may be present creating a cobweb-like appearance.³⁰ The collective findings of a rectal examination of the reproductive tract including ultrasonography, blood progesterone levels, and the clinical history of the cow will allow the most accurate diagnosis regarding the type of cyst present. It is uncommon for blood progesterone levels to be determined in routine cases in clinical practice.

The accuracy with which a skilled palpator can identify the type of cysts present based on palpation alone is relatively poor.³¹ The dynamic nature of both cysts and developing corpora lutea can complicate the diagnosis when palpation alone is used. Farin et al.³² showed that 10% of cows diagnosed as having cysts based on rectal examination were found to have a structure consistent with a normal CL when the ovaries were subsequently examined with ultrasound. When ultrasound technology was used the accuracy of a correct diagnosis of cyst type was 74% for follicular cysts and almost 90% for luteal cysts.³³ Progesterone concentrations have been shown to correlate very well with cyst wall thickness, with 3 mm often being the threshold between follicular and luteal cysts.^1,34 When blood progesterone concentration is combined with both palpation and ultrasound findings, the diagnosis of cyst type approaches 100%, although this too is rarely done due to economic considerations and impracticality in farm situations. Knowledge of progesterone concentrations could certainly aid in treatment decisions, although most of the currently recommended treatments effectively treat both luteal and follicular cysts, thereby negating the need for collecting this information. The added cost of labor and expense to gather this information is not economically justifiable.