Aetiology and pathogenesis of cystic ovarian follicles in dairy cattle

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Aetiology and pathogenesis of cystic ovarian follicles indairy cattle: a review

Tom Vanholder, Geert Opsomer, Aart De Kruif

To cite this version:Tom Vanholder, Geert Opsomer, Aart De Kruif. Aetiology and pathogenesis of cystic ovarian folliclesin dairy cattle: a review. Reproduction Nutrition Development, EDP Sciences, 2006, 46 (2), pp.105-119. <10.1051/rnd:2006003>. <hal-00900607>

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105Reprod. Nutr. Dev. 46 (2006) 105–119© INRA, EDP Sciences, 2006DOI: 10.1051/rnd:2006003

Review

Aetiology and pathogenesis of cystic ovarian follicles in dairy cattle: a review

Tom VANHOLDER, Geert OPSOMER*, Aart DE KRUIF

Department of Reproduction, Obstetrics and Herd Health, Faculty of Veterinary Medicine,Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium

(Received 23 August 2005; accepted 5 December 2005)

Abstract – Cystic ovarian follicles (COF) are an important ovarian dysfunction and a major causeof reproductive failure in dairy cattle. Due to the complexity of the disorder and the heterogeneityof the clinical signs, a clear definition is lacking. A follicle becomes cystic when it fails to ovulateand persists on the ovary. Despite an abundance of literature on the subject, the exact pathogenesisof COF is unclear. It is generally accepted that disruption of the hypothalamo-pituitary-gonadal axis,by endogenous and/or exogenous factors, causes cyst formation. Secretion of GnRH/LH from thehypothalamus-pituitary is aberrant, which is attributed to insensitivity of the hypothalamus-pituitaryto the positive feedback effect of oestrogens. In addition, several factors can influence GnRH/LHrelease at the hypothalamo-pituitary level. At the ovarian level, cellular and molecular changes inthe growing follicle may contribute to anovulation and cyst formation, but studying follicular changesprior to cyst formation remains extremely difficult. Differences in receptor expression between COFand dominant follicles may be an indication of the pathways involved in cyst formation. Thegenotypic and phenotypic link of COF with milk yield may be attributed to negative energy balanceand the associated metabolic and hormonal adaptations. Altered metabolite and hormoneconcentrations may influence follicle growth and cyst development, both at the level of thehypothalamus-pituitary and the ovarian level.

cystic ovarian follicles / pathogenesis / hypothalamus-pituitary / ovary / negative energybalance

1. INTRODUCTION

Cystic ovarian follicles (COF) are animportant cause of subfertility in dairy cat-tle, since they extend the calving interval[1–3]. Prolongation of the calving intervaland treatment costs of COF result in eco-nomic loss for the dairy farmer. In most ofthe literature, COF are referred to as CysticOvarian Disease (COD). However, this ter-minology should be revised since the empha-sis on cystic follicles has shifted over time.

In the 1940’s, the presence of cystic folli-cles on the ovaries was mainly associatedwith nymphomania and a bull-like appear-ance in cows [4, 5], which are clear clinicalsigns of a state of “disease”. Over the pastdecades, dairy herd management and eco-nomics have evolved to a situation in whichfertility in the postpartum period is utterlyimportant. During this period, cystic folli-cles are rather common, and generally occurwithout obvious clinical signs. Normalovarian cyclicity is, however, delayed and

* Corresponding author: [email protected]

Article published by EDP Sciences and available at http://www.edpsciences.org/rnd or http://dx.doi.org/10.1051/rnd:2006003

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106 T. Vanholder et al.

these cysts should therefore be regarded asCOD, despite the absence of previously“classical” signs of disease in the majorityof cases. In addition, after a variable periodof time, cysts can become non-steroido-genic and then they no longer interfere withcyclicity [6, 7]. Consequently, at the timethe non-steroidogenic cyst is observed, noother clinical abnormalities are present.

In present-day dairy herd health pro-grammes, “cysts” are often diagnosed in theabsence of clear clinical signs. Therefore theterm “Cystic Ovarian Disease” no longerseems appropriate and should be replacedby the term “Cystic Ovarian Follicle(s)”which does not necessarily implicate a stateof disease. In this review, we will thereforeuse COF instead of COD. We prefer to useCOF instead of “ovarian cysts”, because theformer term indicates that it is the ovarianfollicle(s) and not any other ovarian tissuethat becomes cystic.

2. DEFINITION

Cystic ovarian follicles develop when oneor more follicles fail to ovulate and subse-quently do not regress but maintain growthand steroidogenesis. They are defined asfollicle-like structures, present on one or bothovaries, with a diameter of at least 2.5 cmfor a minimum of ten days in the absenceof luteal tissue [8–11]. It has become clearthough that this definition needs to berevised. First, the size limit is rather artifi-cial since follicles might already becomecystic at a smaller size, and dominant folli-cles ovulate on average at a size of 1.6 to1.9 cm in dairy cows [12–14]. Moreover,many researchers showed that COF are actu-ally dynamic structures, which can regressand be replaced by new cysts [15–18]. Thefactors that determine whether a cyst willregress or not, remain unknown [19, 20],although changes in mean LH concentra-tion seem to be involved [16]. So therequired individual persistency of ten daysis questionable. In addition, in practice, vet-erinarians generally do not have the oppor-

tunity to perform a second examination ofan animal ten days after the initial diagnosisof COF to fulfill all the terms of the defini-tion. The absence of a corpus luteum isanother requirement, which is not alwaysfulfilled [21]. Non-steroidogenic cysts whichare hormonally inactive do not influencethe normal oestrous cycle, so they can occurtogether with a corpus luteum. Therefore,recent research articles define COF differ-ently and perhaps more logically [16, 22–24],although a generally accepted definition isstill lacking, which can also be attributed tothe heterogeneity (type of cyst, time of occur-rence, clinical signs) of the cysts.

Based on the current knowledge andrecent literature, COF may be defined as fol-licles with a diameter of at least 2 cm that arepresent on one or both ovaries in the absenceof any active luteal tissue and that clearlyinterfere with normal ovarian cyclicity.

Macroscopically, cysts can be subdividedinto follicular and luteal cysts, which areconsidered to be different forms of the samedisorder [25]. Luteal cysts are believed tobe follicular cysts in later stages [26]. Deter-mination of progesterone concentrations inblood plasma, milk or milk fat can help tomake a distinction between the two types.Follicular cysts secrete little or no proges-terone while luteal cysts clearly do [26].However, the threshold values used in theliterature differ a lot [27–31], which makesit difficult to set a concentration threshold.In addition, the many intermediate formswith limited or extensive luteinisation donot allow for a clear identification of cysttype. So classification is not easy and is sub-ject to personal interpretation. Ultrasoundcan be useful in supplying extra information.Follicular cysts have a thin wall (≤ 3 mm)and the follicular fluid is uniformly anecho-genic, while luteal cysts have a thicker wall(> 3 mm), which is visible as an echogenicrim. Also, the latter often have echogenicspots and web-like structures in the follic-ular fluid [32, 33]. Luteal cysts should notbe confused with hollow corpora lutea,which are not pathological at all [26].

Cystic ovarian follicles in dairy cattle 107

Hollow corpora lutea are just young cor-pora lutea with an antrum [34]. Ultrasoundexamination of the ovaries is useful in mak-ing a distinction between a luteal cyst anda cystic corpus luteum [32, 35].

Follicular cysts initially continue to pro-duce oestrogens in the absence of other fol-licles > 5 mm on ultrasound [36]. After avariable period of time oestrogen productionmay cease. The cyst becomes non-steroidog-enic without luteinising, thereby allowing anew follicular wave to emerge and folliclesto grow beyond 5 mm [6, 7].

3. INCIDENCE AND SIGNS

Cystic ovarian follicles can occur at dif-ferent times throughout lactation. The inci-dence varies between 6 and 30% [9, 11, 37–43]. The diagnosis of COF is most oftenmade during the first 60 days post partum[8, 9, 38, 44], mainly because of the closemonitoring of cow fertility during thisperiod. The majority of all cysts occurthroughout this stage [37, 40, 43]. The self-recovery percentage of these early cysts is60–65% [8, 9, 38, 43]. Despite this highself-recovery rate, the importance in dairycow fertility is considerable [45]. Asreported by Thatcher and Wilcox [46] andmore recently by Shrestha et al. [47], earlyresumption of ovarian cyclicity is benefi-cial for fertility. By delaying/interferingwith ovarian cyclicity, COF increase thetime to first insemination and the intervalfrom parturition to conception. In addition,COF decrease the pregnancy rate after firstinsemination and increase the number ofservices per conception [47, 48].

A genetic predisposition exists for COF[49, 50], but the heritability is rather low,being 0.07 to 0.12 [51–53]. However, theincidence in Dutch Holstein Friesian herdsis actually increasing [51]). Genetic selec-tion to reduce the incidence of COF can besuccessful, despite the low heritability [54].

The clinical signs that accompany ovar-ian cysts are variable. Anoestrus is most

common, especially during the postpartumperiod [9]. Irregular oestrus intervals, nym-phomania, relaxation of the broad pelvicligaments and development of masculinephysical traits are other signs which may bepresent, especially later during lactation[11, 55].

4. PATHOGENESIS OF OVARIAN CYSTS

Ovarian dysfunctions like cysts occur mostoften during the early postpartum periodwhen there is a transition from the non-cyclic condition during pregnancy to theestablishment of regular cyclicity. It is gen-erally accepted that cystic follicles developdue to a dysfunction of the hypothalamic-pituitary-ovarian axis. This dysfunction hasa multifactorial etiology, in which genetic,phenotypic and environmental factors areinvolved [9, 19, 26]. When discussing thepathogenesis of COF, a distinction may bemade between a primary defect in thehypothalamus-pituitary and a primary defectat the level of the ovary in the follicle itself.However, COF formation may result fromdefects in both ovary/follicle and the hypoth-alamus/pituitary as well.

4.1. Hypothalamic-pituitary dysfunction

The most widely accepted hypothesisexplaining the formation of a cyst is that LHrelease from the hypothalamus-pituitary isaltered: the pre-ovulatory LH-surge is eitherabsent, insufficient in magnitude or occursat the wrong time during dominant folliclematuration, which leads to cyst formation[8, 16, 18, 41] (Fig. 1). This aberrant LHrelease does not seem to be caused by alower GnRH content of the hypothalamus,nor by reduced GnRH receptor numbers orLH content in the pituitary [56, 57].

It is believed that an altered feedbackmechanism of oestrogens on the hypotha-lamus-pituitary can result in an aberrant


GnRH/LH release and cyst formation. AGnRH/LH surge occurring prematurelyduring follicle growth, i.e. when no folliclecapable of ovulation is present, can renderthe hypothalamus unresponsive to the feed-back effect of oestradiol which results in the

formation of ovarian cysts [22, 58]. To restorethe feedback mechanism, the hypothalamusneeds to be exposed to progesterone [59, 60].Consequently, a similar state of hypotha-lamic refractoriness to oestrogens and sub-sequent cyst formation can be achieved if

Figure 1. Schematic representation of the pathogenesis of ovarian cysts and the possible pathwaysinvolved. An FSH surge stimulates the emergence of a new follicular wave, from which a singledominant follicle is selected at the time of deviation. Through a positive feedback loop oestradiolstimulates GnRH and LH pulsatility, which in turn supports growth and development of the dominantfollicle. Upon reaching preovulatory size, follicular steroidogenic activity reaches a peak and pro-duces a preovulatory oestradiol surge. This surge either fails to elicit a GnRH and subsequent LHsurge or the GnRH/LH surge is mistimed/delayed. The dominant follicle, therefore, does not ovulatebut, due to the ongoing LH pulsatility, continues to grow and becomes a cyst. The disruption of thehypothalamic-pituitary-gonadal axis can be caused by factors affecting the oestradiol feedbackmechanism and GnRH/LH release at the hypothalamic-pituitary level (1) and/or by an aberrant fol-licle growth and development with alterations in receptor expression and steroidogenesis (2), leadingto an altered oestradiol surge and feedback (3). Hypothalamic-pituitary function and folliculargrowth/development may be affected by NEB through metabolic/hormonal adaptations. In addition,in the situation of NEB, the expression of genetic hereditary factor(s) associated with COF may bepromoted or the functional importance may increase, which in turn may affect follicle growth andhypothalamic-pituitary function.


the progesterone rise after a spontaneousovulation is prevented [61]. This physicalstate of hypothalamic unresponsiveness tooestrogens seems to be present in the major-ity of cows with COF, as illustrated by thefailure of an exogenous oestradiol treat-ment to elicit a timely LH surge [62–65].However, the refractoriness of the hypoth-alamus-pituitary for oestradiol in cows withCOF may be a consequence rather than acause of the disease. Removal of the cysticovary by ovariectomy restores the feedbackmechanism and the capacity of oestradiol toelicit an LH surge, although the underlyingmechanism is not known [66].

An altered feedback mechanism andGnRH/LH release may be attributed to factorsinterfering at the hypothalamic-pituitary level.Progesterone at suprabasal concentrationsblocks the LH-surge, thereby inhibiting ovu-lation, but increases the LH pulse frequency[67, 68]. This results in an anovulatory, per-sistent follicle with a larger diameter and alonger lifespan than normal, and increasedperipheral oestradiol concentrations [68].These follicular and hormonal changes arevery similar to observations made in cowswith COF [16]. Recently, Hatler et al. [23]observed that at the time of diagnosis, mostcysts are accompanied by suprabasal pro-gesterone concentrations, which play a rolein cyst turnover. These observations togetherwith the similarities between persistentfollicles, induced by suprabasal progesterone,and naturally occurring cysts, suggest a rolefor progesterone in the pathogenesis of COF.However, suprabasal progesterone profilesseem to play a limited role in primary COFformation [69]. Factors indirectly reducingGnRH/LH secretion like stress [6, 70–72],intrauterine infections [44, 73] and season-ality [74] are also considered to increase therisk of cyst formation.

In cystic cows, the formation of new cystsis accompanied by increased LH pulse fre-quencies and amplitudes [16, 57]. Howeverhypersecretion of LH does not seem to beinvolved in cyst formation, but it may playa role in cyst persistence [75]. Data obtained

in sheep also dismiss an increased LH secre-tion as a primary cause of COF [76].

In conclusion, an aberrant LH surge islikely to be the trigger for the developmentof COF. Abnormal LH release seems to becaused by an altered feedback mechanismof oestrogens on the hypothalamus-pituitary.The malfunctioning of the feedback mech-anism can be caused by factors directly inter-fering at the hypothalamic-pituitary level orby an altered follicle growth and develop-ment disrupting the hypothalamic-pituitary-gonadal axis, as discussed below.

4.2. Ovarian/follicular dysfunction

A primary dysfunction at the level of thefollicle may disrupt the hypothalamic-pitu-itary-ovarian axis and cause the formationof COF (Fig. 1). First of all, alterations inLH receptor expression and content maycause anovulation of the follicle. The LHsurge initiates a complex multi-gene, multi-step process in which timing is essential,finally leading to ovulation of the pre-ovu-latory follicle [77]. According to Kawateet al. [78], FSH and LH receptor numbersin granulosa cells of cysts are decreasedwhen compared to normal follicles, but thisis contradicted by data from Odore et al.[79] and Calder et al. [80]. Discrepanciesbetween studies may be explained by dif-ferences in methodology such as demon-stration of the receptor itself or its mRNA,and the division of cysts into oestrogen-active and oestrogen-inactive. In the samestudy, Calder et al. [80] also studied devel-oping “young cysts” but no differences inFSH/LH receptor mRNA were observedwhen compared to dominant follicles.Young cysts were, however, studied in thepresence of existing cysts, i.e. when theendocrine environment was already altered,and therefore the pathogenesis may differfrom primary developing cysts.

Another receptor of interest is the oestra-diol receptor β (ER-β). In rodents, the impor-tance of this receptor in follicular growth anddevelopment has clearly been demonstrated


[81, 82] and its localisation in follicle cellsthroughout follicular development has beendescribed in many mammals including cat-tle [83, 84]. More specifically, in rat ovarianfollicles ER-β mRNA expression precedesincreased expression of mRNA for the LHreceptor and specific steroidogenic enzymes[85]. Therefore, alterations in ER-β expres-sion may be involved in the development ofCOF. However, this hypothesis is not sup-ported by data from Calder et al. [80] show-ing that ER-β mRNA expression was notaltered in growing young cysts. Odore et al.[79] did, however, find decreased oestrogenreceptor concentrations in follicular cysts,but the oestrogen receptor type was notdefined.

Besides changes in receptor expressionand content, alterations in steroidogenesis bythe dominant follicle may also be involvedin cystic degeneration. After all, the domi-nant follicle has to elicit an LH surge at theright time in its development by producingsufficient oestradiol. Oestrogen-active cystsshow a higher expression of 3β-hydroxy-steroid dehydrogenase mRNA, a steroidog-enic enzyme [80], and cows developing acyst have increased oestradiol concentrationsduring the early stages of follicular domi-nance [86]. However, Calder et al. [80]were unable to observe changes in mRNAexpression of steroidogenic enzymes in thefollicle wall of young growing cysts. Theyconcluded that alterations of the endocrinesystem precede, and perhaps cause, theobserved follicular alterations in cysts. Inthe study of Calder et al. [80], young cystsdid, however, develop in the presence ofexisting cysts, i.e. when the endocrine envi-ronment was already altered. As a conse-quence, the mechanism causing these “youngcysts” to actually become cysts may differfrom the mechanism(s) involved in primarycyst formation.

Apart from changes in mRNA expres-sion for certain receptors and steroidogenicenzymes, cell proliferation and apoptosis inthe granulosa and theca interna cell layersalso seem to be altered in cystic follicles.

Early cystic follicles show an increasein apoptosis while cell proliferation isdecreased [87, 88]. Although it is hard toestablish a cause-effect relationship, alter-ations like these may disrupt normal folliclegrowth and steroidogenesis leading tocystic degeneration.

Recently, Imai et al. [89] suggested thatmatrix metalloproteinases (MMP) could beinvolved in the formation of cysts: higherproMMP-2 and -9 levels were present in thefollicular fluid of cysts than in the follicularfluid of normal dominant follicles. MMPplay a role in follicle wall remodelling andrupture at the time of ovulation [77, 90], buthereto the inactive proMMP form needs tobe transformed to the active MMP form.This activation is triggered by the LH-surge[77]. Since an aberrant LH-surge causesCOF formation, the higher proMMP-2 and-9 levels in the follicular fluid of COF aremost likely an indication of the lack of anLH-surge rather than a cause of COF for-mation.

4.3. Predisposing factors for COF

As mentioned before, COF are mainlyobserved in high yielding dairy cows duringthe first months post partum and milk yieldis generally considered a risk factor [40, 51,88, 86, 91–93], although not all authorsagree [37, 94]. Moreover, besides the factthat a genetic predisposition for COF exists(see above), a genetic correlation betweencysts and milk production traits has beenestablished, indicating that an ongoingselection for production parameters willincrease the incidence of COF [51]. Whatthe genetic factor(s) are and how they pro-mote the formation of cysts is not known.However, the fact that cows do not developa cyst during every lactation and duringevery ovarian cycle indicates that geneexpression may be promoted by, or gainsfunctional importance under, certain stres-sors, for example high milk yield and theassociated negative energy balance (NEB)during the early postpartum period. At this


time, energy requirements to sustain milkyield are higher than energy intake thuscausing a NEB. This NEB is accompaniedby several hormonal and metabolic adapta-tions, affecting ovarian function [95]. Energybalance may be a more accurate parameterthan milk yield to further elucidate the asso-ciation between COF and production traits.Some animals can compensate for highermilk production through greater dry matterintake reducing the effect of milk yield onenergy balance [92]. This could explainwhy not all authors [37, 94] observed a cor-relation between ovarian cysts and milkyield. However, when focussing on energybalance and the occurrence of COF, theresults still remain inconclusive. While Zuluet al. [24], Refsdal [43] and Sovani et al.[96] observed a deeper NEB and increasedmobilization of body reserves in cows devel-oping cysts, Beam [86] noticed that thenadir of the NEB occurred later post partumin cystic cows than in ovulatory cows.Moreover, cystic cows even mobilized lessbody reserves and derived a smaller per-centage of their milk yield from bodyweight loss [86]. Hooijer et al. [97] wereunable to find a more severe NEB, evalu-ated by the fat/protein ratio in milk, in cowswith COF compared to ovulatory cows.However in an earlier study, Heuer et al.[91] observed that a high fat/protein ratio,and, therefore, a more severe NEB, increasedthe risk of cyst occurrence. Data in sheepalso suggest that an increased mobilisationof body reserves, indicative for a deeperNEB, is linked with the occurrence of cysticfollicles [76]. Although a concensus is lack-ing, we conclude from the literature that alink seems to exist between COF and themagnitude and/or duration of the NEB.

The possible underlying mechanism(s)is(are) also still unclear, but NEB mayaffect COF formation at both the level of thehypthalamus/pituitary and the ovary/folli-cle through associated hormonal and meta-bolic changes [98, 99] (Fig. 1). During NEB,peripheral plasma concentrations of IGF-1,insulin, glucose [95] and leptin [100, 101]are reduced, while concentrations of metab-

olites such as non-esterified fatty acids(NEFA) [102] and β-hydroxybutyrate (BHB)are increased [103]. The IGF-system playsan important role in follicle growth anddevelopment [104]. Besides a direct effect,IGF-1 together with insulin indirectly stim-ulates follicular development through upreg-ulation of the LH-receptor on granulosacells [105]. Therefore, low systemic IGF-1concentrations early post partum couldcontribute to anovulation and subsequentdevelopment of cystic follicles as shown byZulu et al. [24]. However, data from Beam[86] do not confirm this hypothesis. Alsoinsulin itself is known to be a potent stim-ulator of follicle cell steroidogenesis andproliferation in vitro [106, 107] and in vivo[108–110]. Consequently, reduced circu-lating insulin concentrations early post par-tum may play a role in ovarian dysfunctioni.e. cyst formation, as we have recentlydemonstrated [69]. Besides low insulin con-centrations, a general state of peripheralinsulin resistance is present as well in highyielding dairy cows early post partum [111,112]. Insulin resistance is regarded as animportant factor in the pathogenesis of thePolycystic Ovary Syndrome (PCOS) inwomen [113–115] and COF have oftenbeen compared to this syndrome, justifiedor not. However, insulin insufficiency ratherthan insulin resistance has been observed inCOF cows [116], indicating an alteredinteraction between glucose and insulin atthe pancreatic level. In addition, in ewes itwas not possible to induce cyst formationthrough the establishment of a state of insu-lin resistance [76]. Conclusively, IGF-1and insulin are important stimulators of fol-licle growth and based on the limitednumber of publications on the subject, lowconcentrations of one or both hormonesmay contribute to the formation of COF(Fig. 2). Further research should confirmwhether or not this hypothesis is valid.

Leptin is a recently “new” hormone, pro-duced by adipocytes, and is regarded as theultimate factor linking metabolic status toreproduction [117]. Depending on the met-abolic state of the animal it either has a


stimulatory effect or none at all on hypoth-alamic-pituitary function in cattle [118–120]. In the postpartum dairy cow, a clearrelationship between leptin profiles andfirst postpartum ovulation is lacking [101],although a minimum permissive level ofleptin seems required to induce the firstpostpartum LH surge [101, 121]. There-fore, leptin may play a role in early post par-tum cyst development.

According to Zulu et al. [24] andHuszenicza et al. [122] cows developingcysts have higher serum NEFA concentra-tions during the first week(s) post partumthan ovulatory cows, although Beam [86]was unable to observe this. Interestingly, inrats, elevated NEFA concentrations for

48 h can decrease insulin secretion by theβ-cells of the pancreatic islets in responseto a glucose challenge [123]. Moreover,NEFA are cytotoxic for several cell types[124–127], including bovine granulosa andtheca cells [128, 129]. So (prolonged) expo-sure to high NEFA concentrations duringperiods of NEB may hamper follicle growthand development, disrupting the complexendocrine system and promoting the forma-tion of ovarian cysts.

Although elevated serum ketone concen-trations increase the risk of delayed cyclic-ity [122, 130, 131] and cyst occurrence [132,133] post partum, they do not exert any neg-ative effects on bovine follicle cells in vitro[134]. Consequently, ketone concentrations

Figure 2. Schematic model of how low insulin and/or IGF-1 concentrations may cause cyst forma-tion. Low insulin/IGF-1 concentrations insufficiently (+) stimulate follicle cell proliferation and oes-tradiol-17β production. The reduced oestradiol-17β feedback, together with the low insulin/IGF-1concentrations result in a reduced gonadotropin release. Dominant follicle growth is retarded andthe altered follicular growth pattern and oestradiol-17β production disrupt the hypothalamo-pitui-tary-gonadal axis. This finally results in an aberrant LH-surge and the subsequent development ofa cystic follicle.


in the postpartum dairy cow seem to be anindicator of the severity of the NEB, but nota mediator of the negative effects of theNEB on reproduction at the ovarian level.

5. CONCLUSION

Cystic ovarian follicles are one of themost frequent and important ovarian disor-ders in modern high yielding dairy cowsthat have been the subject of much researchin recent decades. However, many aspectsof the disease, and especially pathogenesis,remain unclear and inconclusive, as forexample, illustrated by the lack of a cleardefinition. In particular, the endocrine andfollicular changes that precede spontaneouscyst formation are still unknown, mainlydue to the heterogeneity and unpredictabil-ity of the disease. Studies aimed at elucidat-ing the pathogenesis, have tried to do so byinduction of cysts. This, however, may notmimic naturally-occurring cysts. Neverthe-less, such experiments have enhanced ourknowledge about the endocrine and follic-ular changes that occur after cyst formation.Development of an accurate model mim-icking the in vivo situation or identificationof criteria to allow classification of a follicleas a future cyst before it actually becomescystic, would be very valuable in studyingthe cellular and molecular changes that pre-cede ovarian cyst formation.

Due to the genetic correlation with pro-duction traits and the high incidence ofovarian cysts during the period of NEBearly post partum, future research shouldalso focus on the effect of NEB-associatedmetabolic/hormonal changes and energyutilisation on follicular development andsteroidogenesis. Understanding how NEBaffects cyst formation will help to optimisemanagement and feeding practices in pre-venting the occurrence of ovarian cysts/COF.

Further research on cellular changes infollicular cysts may elucidate which genesshow an altered expression pattern com-

pared to normal dominant follicles andcould therefore be involved in the primarydevelopment. Genetic knock-out models aswell may help to determine which genesplay a role in cyst formation. The identifi-cation of these genes would be an initialstep in the process of identifying the hered-itary factor(s), making it possible to genet-ically screen bulls and cows for COF priorto their use in artificial insemination pro-grammes.

ACKNOWLEDGEMENTS

T. Vanholder is supported by a fellowshipfrom the Special Research Fund, Ghent Univer-sity, grant No. 011D8501.

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Aetiology and pathogenesis of cystic ovarian follicles in dairy cattle