Volume 6, Issue 8 March 2009

Reproduction management bulletin

In the Spotlight• Cystic Ovarian Disease/Cystic Ovarian

Follicle in cattle– definition of the

condition

• Incidence and clinical signs

• Pathogenesis of Cystic Ovarian Follicles

formation:

- Hypothalamic-pituitary dysfunction

- Ovarian/follicular dysfunction

• Factors predisposing to COF

• Leading directions for the treatment

of COF/COD in cattle

CYSTIC OVARIAN FOLLICLES IN DAIRY CATTLE

Prof. Dr. Geert OpsomerDepartment of Reproduction, obstetrics and Herd Health, Faculty of Veterinary Medicine, Ghent University, Salisbury-laan 133, 9820 Merelbeke, Belgium Geert.Opsomer@UGent.be

Department of Reproduction, Obstetrics

and Herd Health Faculty of Veterinary

Medicine, Ghent University, Belgium

IntroductionCystic ovarian follicles (COF) are an im-

portant cause of subfertility in modern

dairy cattle. Prolongation of the calving

interval and treatment costs of COF result

in economic losses for the farmer. In the

past COF was mainly associated with clini-

cal symptoms such as nymphomania, and

was therefore usually called Cystic Ovar-

ian Disease (COD). Nowadays it is mainly

seen as a cause of anoestrus leading to

an increased interval parturition-first in-

semination without any obvious clinical

symptoms. Therefore, we currently pre-

fer to use the term COF instead of COD.

DefinitionCystic ovarian follicles develop when one

or more follicles fail to ovulate and subse-

quently do not regress but maintain their

growth. They commonly are defined as

follicle-like structures, present on one

or both ovaries, with a diameter of at

least 2.5 cm for a minimum of ten days

in the absence of a corpus luteum. It has

become clear though that this definition

needs to be revised.

First, the diameter limit is rather artifi-

cial since follicles might already become

cystic at a smaller size. Moreover, many

researchers demonstrated that COF are

actually dynamic structures which can re-

gress and be replaced by new cysts. The

factors that determine whether a cyst will

regress or not remain unknown, although

changes in the mean LH concentrations

seem to be involved. The required persis-

tency of ten days is also questionable. In

addition, in practice, veterinarians gener-

ally do not have the opportunity to per-

form a second examination of an animal

ten days after the initial diagnosis.

The absence of a corpus luteum is anoth-

er requirement to fulfill the definition.

It is however shown that some hormon-

ally inactive cysts do not influence the

oestrous cycle and hence can be found

in the presence of a corpus luteum. This

kind of cysts not influencing the oestrous

cycle and hence not being pathological is

therefore called ‘indifferent cysts’.

As a conclusion, it is clear that due to the

heterogeneity of the cysts it is very dif-

ficult to come to a generally acceptable

definition. Based on our current knowl-

edge and recent literature, COF can be

defined as follicles with a diameter of

at least 2 cm that are present on one or

both ovaries in the absence of a corpus

luteum and that clearly interfere with

normal ovarian cyclicity.

Macroscopically, cysts can be subdivided

into follicular and luteal cysts, which are

considered to be different forms of the

same disorder. Luteal cysts are by some

authors believed to be follicular cysts in

later stages. As follicular cysts secrete

very little or no progesterone while luteal

cysts clearly do, determination of proges-

terone in plasma or milk(fat) is the main

method to make a distinction between

the two types of cysts.

Reproduction management bulletin

Also ultrasound can be useful to differ-

entiate these two types of cystic struc-

tures. Follicular cysts have a thin wall

(≤3mm), and the follicular fluid is usu-

ally uniformly anechogenic, while luteal

cysts have a thicker wall (≥3mm) which

is visible as an echogenic rim. Also, the

latter often have echogenic spots and

web-like luteal structures in the follicu-

lar fluid.

Luteal cysts should however not be con-

fused with hollow ‘cystic’ corpora lutea

which are not pathological as they do

not disrupt the normal cyclicity at all.

Some authors however neglect the im-

portance of making the differential di-

agnosis between a luteal and a follicular

cyst, as the response of both types of

cysts to a standard GnRH treatment is

similar.

Incidence and clinical singsCystic ovarian follicles can occur at dif-

ferent times throughout lactation. Re-

ports on their incidence vary between 6

and 30%. Diagnosis of COF is most often

made during the first 60 days of lactation,

mainly because of the close monitoring

of the postpartum cows. The cysts occur-

ring during the early postpartum period

do however have a self recovery percent-

age of 60% or even higher. As the treat-

ment of COF is reported to be very suc-

cessful and rather cheap, authors usually

advice to treat the affected animals in

stead of waiting for self recovery as the

latter may in some cases lead to signifi-

cantly increased intercalving intervals.

The incidence of COF also depends on

parity. As described by several indepen-

dent authors, the lactational incidence

rate was significantly higher in multipa-

rous cows (±15%) in comparison with

heifers (±7%).

A genetic predisposition exists for COF

but the heritability is rather low (0.07 to

0.12). Authors mentioned that although

the heritability is low, genetic selec-

tion against COF has been successful.

Clinical signs that accompany ovar-

ian cysts are variable. Anoestrus is most

common, especially during the postpar-

tum period. Irregular oestrous intervals,

nymphomania, relaxation of the broad

pelvic ligaments and development of

masculine physical traits are other signs

which may be present, especially later in

lactation.

Pathogenesis of COFOvarian dysfunction, such as cysts occur

most often during the early postpartum

period when the transition from the

noncycling condition during pregnancy

to the resumption of regular cyclicity

after calving takes place. It is generally

accepted that cystic follicles develop due

to a dysfunction of the hypothalamic-

pituitary-ovarian axis. This dysfunction

has a multifactorial etiology in which

genetic, phenotypic and environmental

factors are involved. When discussing

the pathogenesis of COF, a distinction

should be made between a primary de-

fect in hypothalamus-pituitary function

from the problems at the level of the

ovary.

Hypothalamic-pituitary dysfunction

The most widely accepted hypothesis

explaining the formation of a cyst is the

one stating that the LH release from the

hypothalamus-pituitary axis is altered:

the pre-ovulatory LH-surge is either ab-

sent, insufficient in magnitude or occurs

at the wrong time during dominant fol-

licle maturation, finally resulting in cyst

formation. The aberrant LH release does

not seem to be caused by a lower GnRH

content of the hypothalamus, nor by re-

duced GnRH receptor numbers or LH con-

tent in the pituitary.

It is believed that an altered feedback

mechanism of oestrogens on the hypo-

thalamus-pituitary can result in an aber-

rant GnRH/LH release and hence in cyst

formation. A GnRH/LH surge occurring

prematurely during follicular growth, i.e.

when no follicle able to ovulate is pres-

ent, can render the hypothalamus unre-

sponsive to the feedback effect of oes-

tradiol which results in the formation of

ovarian cysts.

An altered feedback mechanism and

GnRH/LH release may be attributed to

factors interfering at the hypothalamic-

pituitary level. Progesterone at supra-

basal levels blocks the LH-surge, thereby

inhibiting ovulation but increasing the

LH pulse frequency. This results in an

anovulatory, persistent follicle with a

larger diameter and a longer lifespan

than normal, very similar to COF. In early

postpartum cows, the suprabasal periph-

eral progesterone levels may originate

from the release of progesterone by the

breakdown of fat during the negative en-

ergy balance (NEB). During late gestation

when cows are in the anabolic phase and

are building their fat depots as energy

reserves for the next lactation, they also

have high progesterone levels to sustain

pregnancy. As progesterone is lipophil-

ic, it will be deposited in the fat at that

time of lactation. In the early postpar-

tum phase however, cows enter NEB and

break down their fat reserves as a source

of energy. In this way released progester-

one may cause suprabasal progesterone

levels and lead to COF formation.

Reproductive tract of a cow with follicular

ovarian cyst

Bovine ovary with thick walled luteal cysts

Reproduction management bulletin

Other factors known to (in)directly

inhibit GnRH/LH pulse secretion at

the exact moment in relation to the

growth and maturation of the domi-

nant follicle, and in this way elicit

cysts are stress, intrauterine infec-

tions and seasonality.

In conclusion, an aberrant LH surge is

likely to be the trigger for the devel-

opment of COF. Abnormal LH release

seems to be caused by an altered

feedback mechanism of oestrogens

on the hypothalamus-pituitary axis.

Ovarian/follicular dysfunction

Also a primary dysfunction at the

level of the follicle may disrupt the

hypothalamic-pituitary-ovarian axis

and through this cause the formation

of COF. First of all, alterations in LH

receptors expression and content in

the follicle may cause anovulation.

Besides the changes in receptors ex-

pression and content, alterations in

steroidogenesis by the dominant fol-

licle may also be involved in cystic de-

generation. After all, the dominant

follicle has to stimulate an LH surge

at the right time in its development

by producing sufficient amounts of

oestrogens. Aberrations in mRNA

expression of steroidogenic enzymes

have been demonstrated in cystic fol-

licles.

Apart from the changes in mRNA

expression for certain receptors and

steriodogenic enzymes, cell prolif-

eration and apoptosis in the granu-

losa and theca interna cell layers also

seem to be altered in some cystic fol -

licles. In our lab we recently demon-

strated that elevated NEFA levels as

occurring in dominant follicles early

after calving have a significant nega-

tive effect on the proliferation of

granulosa and theca interna cells in

vitro. Especially the saturated fatty

acids like stearic acid (18:0) and pal-

mitic acid (16:0) caused a diminished

proliferation and a higher apoptosis

of the oestrogen producing follicular

cells. The latter may be an important

factor in the pathogenesis of COF

since a reduced viability of these fol-

licular cells may be accompanied with

oestrogen levels that are too low to

cause an LH surge at the exact mo-

ment.

As insulin has been shown to be an

important factor that stimulates fol-

licular cells to proliferate and produce

oestrogens, the remarkably steep de-

crease of peripheral insulin levels in

high yielding dairy cows early after

calving can also be seen as an attrib-

utable factor in the pathogenesis of

COF. Indeed, in a field study recently

published by our group we were able

to demonstrate that in some cows

suffering from COF, the peripheral in-

sulin levels near the moment of cyst

formation were significantly lower

than in control cows which did ovu-

late. Earlier, we had demonstrated

using intravenous glucose tolerance

tests (IVGT) that in some cows suf-

fering from COF there was no insulin

response at all after the cows were

given a glucose bolus.

As a conclusion, factors that have a

negative effect on the production of

oestrogens by the follicular granu-

losa and/or theca interna cells can

be seen as significant contributors to

the establishment of COF. High NEFA

levels (especially of saturated fatty

acids) and low insulin levels seem to

act in this way and seem to be impor-

tant risk factors to elicit COF.

Predisposing factors for COFAs mentioned earlier, COF are mainly

observed in high yielding dairy cows

during the first months post partum

and high milk yield is generally con-

sidered as a risk factor, although not

all authors agree in this. Moreover,

besides the fact that a genetic pre-

disposition for COF exists, a genetic

correlation between cysts and the

level of milk production has been es-

tablished, indicating that an ongoing

selection for production will increase

the incidence of COF.

What the genetic factors are and how

they promote the formation of cysts is

however not known. However, the fact

that cows do not develop a cyst during

each lactation and during each ovarian

cycle indicates that gene expression may

be promoted by certain stressors like for

example high milk yield and the herewith

associated NEB. A lot of studies have

been done in order to find a correlation

between the level of milk production, the

herewith associated NEB and the occur-

rence of COF. Although a strict consensus

is lacking, we conclude from the litera-

ture that a link seems to exist between

COF and the magnitude and/or duration

of the NEB accompanying the current lev-

el of milk production. Etiologic factors in-

volved may be lowered levels of glucose,

insulin and IGF1 or elevated NEFA levels

as explained in more detail earlier.

Other significant risk factors are parity,

puerperal diseases like metritis and clini-

cal mastitis and (extreme) stress factors.

In conclusion, it can be stated that factors

influencing the development of COF are

still not fully understood. A major prob-

lem is that most studies measure hor-

mone levels only after the condition had

been diagnosed. Moreover, significant

correlations do not necessarily indicate a

causative relationship.

Treatment of COFOnce the diagnosis of COF is made, the cli-

nician has to take the decision either to do

nothing and hope for spontaneous recovery,

to administer a general hormonal treatment,

or to try to differentiate the type of cyst and

administer a more specific treatment. Re-

COF are mainly observed in high yielding dairy

cows during the first months post partum

Reproduction management bulletin

gardless of the treatment decision, the aim

of the therapy is to re-establish normal oes-

trous cycles as soon as possible by choosing

the most economical treatment. It has been

demonstrated that it usually is more econom-

ical to treat ovarian cysts than to hope for a

spontaneous recovery.

On the basis of the hypothesis that an ab-

sence of the LH pulse is the primary cause

of COF, general treatment of cows affected

by COF is directed to stimulate luteinization

of the cyst which is usually followed by the

re-establishment of a normal oestrous cycle.

Biological preparations high in LH-like activity

(e.g. human chorionic gonadotrophin) and

exogenous GnRH, which acts on the pituitary

gland to cause the release of endogenous LH,

have been widely and effectively used for the

treatment of both follicular and luteal cysts.

Results of both treatments are comparable.

Around 80% of the treated cows exhibit a

fertile oestrus within 16 to 30 days, although

pregnancy rates are slightly lower in compari-

son with those of normal cows. Since both

types (luteal and follicular) of cysts respond

similarly to this kind of treatment, differentia-

tion is not necessary and authors agree that

this approach remains the best initial therapy

for the majority of cows with COF regardless

of their type.

Prostaglandin therapy is also used to treat

cows with luteal cysts. The response of ovar-

ian cysts to this kind of treatment depends

on the presence of luteal tissue and the

veterinarian’s ability to recognize it. Because

palpation per rectum has been reported to

be an inaccurate method for differentiation,

the diagnosis has to be based on the deter-

mination of progesterone in plasma or milk,

or on the use of ultrasonography. Although

the treatment with luteolytic drugs results in

a shorter interval to a fertile oestrus the cost-

benefit evaluation of this kind of treatment

has to incorporate the surplus costs of the im-

mediate cyst differentiation. In this regard, it

has been demonstrated that the practice of

identifying all cysts as either follicular of luteal

prior to treatment is questionable from an

economic point of view. It has also been sug-

gested that the use of prostaglandins given 9

to 14 days after GnRH may shorten the inter-

val from treatment to the first fertile oestrus

by about 12 days, yielding shorter intervals to

conception than when GnRH is used alone.

While doing the latter, one should take into

account the cost of the double treatment

which is another economical drawback.

Cows not responding to GnRH treatment

can be treated with progesterone with fairly

good results. Although the mechanism by

which progesterone causes regression of the

ovarian cyst is not well established, it has been

suggested that this treatment suppresses the

release of LH, resulting in an accumulation

in the pituitary and leading to an enhanced

surge of LH when the progesterone treat-

ment is withdrawn.

As the treatment results by simply injecting

affected cows with GnRH or LH-agonists are

reported to be relatively high, treatments

based on (manual) rupture of the cyst are

currently seen as outdated. Rupturing the

cyst may lead to excessive bleeding especially

in luteal cysts, and/or in the excessive forma-

tion of fibrin leading to the establishment of

adhesions involving the ovary. The latter may

negatively affect pregnancy rates once the

cows are inseminated.

Reproduction management bulletin

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