2009: Cystic ovarian disease in dairy cattle Cystic ovarian disease in dairy cattle 1 J. D. Smith 2 Department of Pathobiology and Population Medicine, College of Veterinary Medicine, 3 Mississippi State University, Mississippi State, MS, USA 4 5 Abstract 6 Practitioners involved in the delivery of veterinary care and who provide 7 consultation to dairy cattle owners must be able to effectively diagnose and treat common 8 conditions which impact the economic stability of the dairy enterprise. This manuscript 9 provides the practitioner with the information to understand the pathophysiology of 10 cystic ovarian disease, choose an appropriate treatment and suggest possible management 11 changes to minimize the economic impact of this disorder. 12 Keywords: Cystic ovarian disease; anestrus; infertility; GnRH; cattle 13 Introduction 14 Cystic ovarian disease (COD) has been recognized as a frequent cause of 15 subfertility and poor reproductive efficiency in cattle for almost 100 years and is still 16 considered to be one of the most economically important reproductive conditions 17 affecting dairy cattle worldwide. The major causes of economic loss are due to increased 18 days open in the postpartum period which extends the calving interval, costs associated 19 with treatment and higher culling rates in affected animals.1,2 Cystic ovarian disease has 20 also been shown to decrease the pregnancy rate to subsequent AI which leads to an 21 increase in services per conception resulting in increased semen costs.3 22 Terms which have been used to describe the condition of persistent anovulation of 23 preovulatory follicles include: cystic ovarian disease, cystic ovarian follicles, cystic 24 ovarian degeneration and cystic ovaries. The most common term used in the literature to 25 describe this condition is cystic ovarian disease. As we understand more about this 26 253 condition and management practices have changed we should revisit the use of the term 27 cystic ovarian disease. The most recent term used to describe this ovarian dysfunction is 28 cystic ovarian follicles (COF).1,3 Since “cysts” are often diagnosed in the absence of any 29 obvious clinical signs the term “disease” should likely be replaced by “follicles” as it 30 more accurately describes the condition.3 31 Definition 32 The classical definition of COD in cattle is the presence of an anovulatory 33 structure on the ovary which is > 2.5cm in diameter and has persisted for at least 10 days 34 in the absence of a corpus luteum (CL).4 As more knowledge is gained regarding COD 35 the previous definition requires refinement. The size limit of 2.5cm is arbitrary and 36 would exclude cystic follicles which are smaller than 2.5cm. The dominant follicle of 37 dairy cattle typically ovulates on average at a size of 1.6-1.9cm.3 The classic definition 38 that requires presence for 10 days should also be questioned due to the fact that cystic 39 ovarian follicles have been shown to be dynamic structures which change over the course 40 of time. Also cows diagnosed with COD are generally not palpated again in 10 days to 41 totally fulfill the classical definition. The necessity for the absence of a CL is also not 42 universally fulfilled. Cysts which are non-steroidogenic and thus hormonally inactive 43 may not influence the estrous cycle and thus could be found in the presence of a CL. 44 Most cows today however are diagnosed with COD on the basis of a single rectal 45 palpation or ultrasound examination and no attempt is made to assure the structure has 46 been present for 10 days in the absence of a CL. 47 A recent term and definition put forth in the literature to more accurately describe 48 this condition is cystic ovarian follicles. Cystic ovarian follicles are defined as follicles 49 254 with a diameter of at least 2 cm that are present on one or both ovaries in the absence of 50 any active luteal tissue and that clearly interferes with normal ovarian cyclicity.3 This 51 definition more clearly defines the condition in relation to our current understanding and 52 its impact on reproduction. 53 Cysts are further classified as being follicular cysts or luteal cysts depending on 54 the degree of lutenization and the level of progesterone secretion. Both are considered to 55 be different forms of the same condition with luteal cysts being a follicular cyst which 56 has undergone some lutenization.2 Follicular cysts do not secrete progesterone whereas 57 luteal cysts secrete varying amounts of progesterone however an absolute threshold has 58 not been determined.3 The ability to accurately classify each cyst is subject to personal 59 interpretation based on clinical as well as laboratory findings. 60 Ultrasound can be a very useful tool with which to gather information regarding 61 the classification of cysts. Follicular cysts typically have a thin wall (≤ 3 mm) whereas 62 luteal cysts typically have a thicker wall (≥ 3 mm). The follicular fluid is often 63 hypoechoic in follicular cysts whereas in luteal cysts it may contain echogenic strands 64 creating a web-like appearance.5 65 Incidence 66 The incidence of COD in dairy cattle varies amongst several studies but is 67 typically between 5-19% with mean of 10-12%.2 The incidence of COD could likely be 68 even higher based on the findings that as many as 60% of cows that develop COD 69 recover spontaneously prior to their first postpartum ovulation and could easily remain 70 undiagnosed. The majority of COD is diagnosed by routine rectal palpations during the 71 first 60 days postpartum at which time cows are being examined prior to breeding. Cases 72 255 are also commonly diagnosed between 120-210 days postpartum. These cases are 73 typically diagnosed in cows which have been presented for examination after extended 74 periods of anestrus. 75 There is a genetic predisposition for COD in dairy cattle, however the heritability 76 is low at 0.07 to 0.12.6,7 Cystic ovarian disease seems to occur more often in certain cow 77 families. Genetic selection attempting to remove sires who produced daughters that 78 developed COD from the breeding pool has been shown to significantly reduce the 79 incidence of COD in Swedish herds.3 Reduction in the incidence from 10% to 3% was 80 achieved by selection against sires that produced daughters with COD.8 Genetic 81 selection as a prevention for COD will be a lengthy endeavor due to the low heritability 82 but can be effective. 83 With routine use of synchronization programs (i.e., Pre-sync, Ovsync) during the 84 voluntary waiting period to synchronize the first postpartum AI the incidence of COD as 85 diagnosed by rectal palpation could likely be lower than previous studies have identified. 86 However, as the modern dairy cow is under tremendous dietary and production stressors 87 which can predispose her to COD the apparent affect of these programs on clinical 88 incidence may be modulated. 89 Clinical signs 90 Behavioral signs seen in cows with COD are variable but can generally be 91 classified into two groups, anestrus and nymphomania. The most common clinical sign 92 observed in cows with COD is anestrus, this is especially evident in the early postpartum 93 period. Approximately 80% of cows that develop COD early in the postpartum period 94 exhibited anestrus.4 These cows are often presented for examination after failure of the 95 256 herdsman to detect normal postpartum cycling activity. Nymphomania is yet another 96 clinical sign which can be seen in cows with COD. These cows often attempt to ride 97 other cows but generally will not stand for mating themselves.4 Approximately 10% of 98 cows affected with COD show signs of nymphomania. It appears that as the number of 99 days following calving at which COD is diagnosed increases the likelihood of 100 nymphomania being a clinical observation also increases.4 Irregular estrous cycles can 101 also frequently occur in cows with COD which often leads to inappropriate breeding of 102 these cows based on poor or weak signs of estrus. 103 Pathogenesis 104 A dysfunction in the normal hypothalamic-pituitary-gonadal axis leading to 105 ovulation failure is the most common accepted mechanism of COD.1,2,9-11 The precise 106 mechanisms leading to the aforementioned dysfunction have yet to be fully elucidated. It 107 is believed that there is a multi-factorial cause with genetic, phenotypic, environmental 108 and management factors involved.3 109 The most widely accepted hypothesis involves the altered release of luteinizing 110 hormone (LH) from the pituitary gland. The pre-ovulatory surge of LH is either absent, 111 insufficient in magnitude or is improperly timed whereas the dominant follicle does not 112 ovulate leading to cyst formation.1-3 There does not appear to be a reduction in GnRH 113 content in the hypothalamus or a reduction in GnRH receptors in the pituitary.3 114 Luteinizing hormone content in the pituitary also does not appear to be reduced in cows 115 with COD.3,12 Normally pre-ovulatory follicles secrete estrogen which has a positive 116 feedback on the hypothalamic-pituitary axis causing release of LH which is responsible 117 for the subsequent ovulation. There appears to be a lack of responsiveness of the 118 257 hypothalamus to the positive feedback mechanism of estrogen leading to the altered 119 release of GnRH and/or subsequently LH causing the anovulatory state of COD. 120 Predisposing factors 121 Numerous factors have been associated with the development of COD in cows. 122 This condition appears to more commonly affect high producing dairy cows in their 123 second through fifth lactation. Early in lactation when the cow is often in a negative 124 energy balance metabolic disturbances are more common and are often followed by 125 COD. There appears to be a higher incidence of COD during winter months, however 126 photoperiod does not appear to have an effect on the hypothalamic-pituitary-ovarian 127 (HPO) axis. Other factors which have been associated with depression of GnRH/LH 128 release and subsequent cyst formation include uterine infections, retained fetal 129 membranes, lameness and stress.3,11 Postpartum uterine infections are thought to 130 stimulate cortisol secretion which can suppress the pre-ovulatory surge of LH leading to 131 anovulation and subsequent cyst formation.1 The associated endotoxins and 132 inflammatory mediators can disrupt the normal hormonal pathways that ultimately 133 control ovarian function including ovulation.13 The role of stress in COD is believed to 134 be related to the release of cortisol which appears to block the estrogen induced LH 135 surge.1,10,14 136 Diagnosis 137 The diagnosis of COD has historically been made based on the finding during 138 rectal examination of the cow along with her reproductive history. However the 139 collective findings of a rectal examination, an ultrasonographic evaluation of the 140 reproductive tract including the ovaries, progesterone concentrations in blood or milk and 141 258 behavioral abnormalities will allow for a more accurate diagnosis. The accuracy with 142 which a skilled palpator can identify the type of cysts based on palpation alone is 143 relatively poor.15 The dynamic nature of both cysts and developing corpora lutea can 144 complicate the diagnosis when palpation alone is used. A study by Farin et al., showed 145 10% of cows that were diagnosed as having cysts based on rectal examination were found 146 to have a structure consistent with a normal corpus luteum by transrectal ultrasound 147 examination.16 In one study evaluating the use of ultrasound the accuracy of a correct 148 diagnosis being made was 74% of follicular cysts and almost 90% of luteal cysts.17 149 Progesterone concentrations have been shown to correlate very well with cyst wall 150 thickness with 3 mm being the threshold between follicular and luteal cysts.1,18 When 151 one combines progesterone concentrations in addition to rectal examination and 152 ultrasound findings the accuracy of diagnosis of the cyst type approaches 100% however 153 this is rarely done outside of research settings. Although using progesterone testing to 154 accurately determine the cyst type would aid in treatment decisions it is rarely used in 155 practice situations due to the economic considerations. 156 Treatment options 157 Probably the oldest treatment of COD in cattle is manual rupture of the cyst via 158 rectal palpation. With the advances in our understanding of COD and the availability of 159 effective medical options this treatment can no longer be recommended. The possibility 160 of oviductal or ovarian bursal adhesions arising secondary to the trauma associated with 161 manual rupture and their affects on subsequent fertility are too great to ignore.4 162 Hormone therapy aimed at either causing (GnRH) or mimicking (human 163 chorionic gonadotropin; hCG) an LH surge can be used to treat follicular cysts. Of these 164 259 two, GnRH is generally chosen first due to its small molecular size which reduces the 165 likelihood of an immune reaction.1,10 After an injection of GnRH a surge of LH from the 166 pituitary occurs within 2 hours.19 This LH surge can cause lutenization of follicular 167 cysts which will undergo spontaneous luteolysis in about 18 days at which time a normal 168 estrous cycle begins. Another possibility following GnRH treatment in cows with 169 follicular cysts is ovulation of a dominant follicle followed by a subsequent normal luteal 170 phase. Since cystic cows continue to have follicular waves, the response to GnRH is 171 likely due to ovulation of a dominant follicle present with recruitment of a new cohort of 172 follicles rather than lutenization or regression of the cysts.20 The subsequent increase in 173 progesterone concentrations causes the re-setting of the normal HPO axis and resumption 174 of normal cyclicity in most cows. In one study that evaluated the effectiveness of a 175 single injection of GnRH for treatment of cows with ovarian cysts, 72% of cows resumed 176 normal cycling within 20 days of treatment compared to 16% of control cows.19 177 However other studies have not borne out the same results. A study that evaluated the 178 effectiveness of GnRH as a sole treatment for follicular cysts showed no difference in 179 treated animals versus controls. The lack of agreement between numerous studies 180 evaluating the efficacy of GnRH is likely due to the lack of control animals and the 181 number of cows which recover spontaneously. There was no difference in the period of 182 time between treatment with GnRH and resolution of the cyst or in the period of time 183 until a CL was evident.21 This study brings to light the high incidence of spontaneous 184 recovery and somewhat brings into question the effectiveness of GnRH alone as a sole 185 treatment for cows with COD. Timing of treatment in the postpartum period does not 186 appear to affect treatment response. In one study, cystic cows were treated with GnRH 187 260 either before or after 60 days following calving. There was no difference in treatment 188 response in the two groups however there were no control animals with which to 189 compare.22 In accurately diagnosed cases a relatively large percentage of cows return to 190 cyclicity following an injection of GnRH, however some of this response could be 191 attributed to spontaneous resolution. 192 A recent pharmacokinetic study attempted to find the optimal dose of GnRH for 193 treatment of cows with COD. The dose of GnRH which was found to guarantee 194 production of a critical maximum plasma LH concentration of 5 ng/ml was 74 ug of 195 GnRH.23 Therefore the standard 100 ug dose of GnRH used to treat cows with COD was 196 found to generate a LH concentration of 5.86 ng/ml and should be adequate in most cases 197 of COD. 23 198 Human chorionic gonadotropin has been used successfully to treat refractory 199 follicular cysts that fail to respond to GnRH. It has LH-like properties and causes the 200 cyst to lutenize and begin producing progesterone. Once the cyst has lutenized it can 201 then be treated with prostaglandin to restore the normal cyclical pattern. Its use is often 202 relegated to cases in which GnRH has failed to render a cure. Its use has occasionally 203 been noted to stimulate an immune reaction however the importance of this reaction is 204 poorly understood.1 205 Prostaglandin is the treatment of choice for luteal cysts and cysts that have 206 undergone lutenization after being treated with GnRH or hCG.1,2,10,20 Prostaglandin has 207 no effect on follicular cysts so it is important to accurately diagnose the type of cyst 208 before using prostaglandin alone. After prostaglandin administration luteal cysts regress 209 with estrus occurring in 90% of cows by day 8 post treatment. Prostglandin is commonly 210 261 used in the treatment of cysts after a previous injection of GnRH as part of an Ovsync 211 protocol. 212 Protocols involving a series of hormonal injections aimed at treating the cysts and 213 restoring the cow to normal cyclicity have been proposed.1,11,24-27 The classical Ovsync 214 protocol has been employed as a treatment for cysts irrespective of their type. The 215 rational in using an Ovsync protocol is to both treat the cyst and eliminate estrus 216 detection and breed the cows with timed AI.11,24-27 Progesterone levels in cows with 217 COD which are treated with GnRH are elevated five days after treatment and therefore 218 could be treated with traditional Ovsync with good results.24 When cows with COD are 219 subjected to the Ovsync protocol pregnancy rates to subsequent timed insemination has 220 range from 17-25%.25,28 221 Use of progesterone as a treatment for cows with COD has been proposed for 222 over 40 years.29 Now that progesterone impregnated vaginal pessaries have been 223 approved for use in lactating dairy cattle in the United States recent emphasis has been 224 placed on their use in the treatment of COD. Progesterone administration has been 225 shown to re-establish the normal feedback mechanisms involving the HPO axis and allow 226 cows with COD to resume normal cyclicity. The duration of progesterone treatment 227 which is sufficient to re-establish normal hypothalamic responsiveness to estradiol 228 appears to be as short as three days.30 There was no difference in the pregnancy rates of 229 dairy cattle with COD when treated with either the Ovsync protocol or use of a 230 progesterone-releasing pessary for seven days with prostaglandin administration at the 231 time of pessary removal followed by breeding after heat detection suggesting that use of 232 intravaginal progesterone as a treatment for COD can be effective.27 Use of 233 262 progesterone-releasing pessaries in combination with the Ovsync protocol has been 234 studied as a treatment for cysts as well. Results showed an increase in pregnancy rates in 235 cystic cows treated with Ovsync plus progesterone (37.5% pregnancy rate) compared to 236 Ovsync alone (16.7% pregnancy rate).26 237 In a recent study, the effectiveness of the opioid antagonist naloxone as a 238 treatment for cows with COD was examined.31 It has been shown that stress may be a 239 contributor to the pathogenesis of COD in cattle. Endogenous opioid peptides are 240 involved in many responses to stress including the regulation of various endocrine 241 systems.31 Endogenous opioid peptides are believed to block the release of GnRH from 242 the hypothalamus as well as the estrogen-induced LH surge.14 It has been shown that 243 administration of the opioid antagonist naloxone results in elevated LH release in cattle 244 under various physiological states.32 Cows diagnosed with COD were treated with 245 naloxone as well as the GnRH agonist buserelin. In this study 77.5% of treated cows had 246 begun cystic regression as viewed with ultrasonography or had begun cycling normally 247 within two weeks post-treatment.31 Further investigation of the use of naloxone is 248 warranted and specifically its use in the absence of GnRH products which confound the 249 interpretation of this particular study. 250 Conclusion 251 Cystic ovarian disease remains an important postpartum condition affecting dairy 252 cattle with a substantial economic impact on the modern dairy farm. Although much 253 effort and research has been placed on elucidating the precise mechanism(s) leading to 254 COD its exact cause remains unclear. Currently the most effective treatments for COD 255 appear to be those which are capable of resetting the HPO axis thereby re-establishing 256 263 normal feedback mechanisms which results in normal cyclical patterns. Both the Ovsync 257 protocol, the use of intravaginal progesterone, or the combination of the two appear to be 258 the most practical and effective treatments for most modern dairy operations. Due to the 259 fact of a high incidence of spontaneous recovery in cows with COD it has made it 260 difficult to interpret apparent response to various therapies. Further research into the 261 cellular and molecular events that are occurring in cows with COD and the interactions of 262 various stressors will hopefully provide us more answers to this very common condition. 263 References 264 1. Peter AT: An update on cystic ovarian degeneration in cattle. Reprod Dom Anim 265 2004;39:1-7. 266 2. Garverick HA: Ovarian follicular cysts in dairy cattle. J Dairy Sci 1997;80:995-267 1004. 268 3. Vanholder T, Opsomer G, Kruif A: Aetiology and pathogenesis of cystic ovarian 269 follicles in dairy cattle: a review. Reprod Nutr Dev 2006;46:105-119. 270 4. 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J Anim Sci 350 1992;70:2794-2800. 351 352 353 268 << /ASCII85EncodePages false /AllowTransparency false /AutoPositionEPSFiles true /AutoRotatePages /All /Binding /Left /CalGrayProfile (Dot Gain 20%) /CalRGBProfile (sRGB IEC61966-2.1) /CalCMYKProfile (U.S. Web Coated \050SWOP\051 v2) /sRGBProfile (sRGB IEC61966-2.1) /CannotEmbedFontPolicy /Warning /CompatibilityLevel 1.4 /CompressObjects /Tags /CompressPages false /ConvertImagesToIndexed true /PassThroughJPEGImages true /CreateJobTicket false /DefaultRenderingIntent /Default /DetectBlends true /DetectCurves 0.0000 /ColorConversionStrategy /CMYK /DoThumbnails false /EmbedAllFonts true /EmbedOpenType false /ParseICCProfilesInComments true /EmbedJobOptions true /DSCReportingLevel 0 /EmitDSCWarnings false /EndPage -1 /ImageMemory 1048576 /LockDistillerParams false /MaxSubsetPct 100 /Optimize true /OPM 1 /ParseDSCComments true /ParseDSCCommentsForDocInfo true /PreserveCopyPage true /PreserveDICMYKValues true /PreserveEPSInfo true /PreserveFlatness false /PreserveHalftoneInfo false /PreserveOPIComments false /PreserveOverprintSettings true /StartPage 1 /SubsetFonts true /TransferFunctionInfo /Apply /UCRandBGInfo /Preserve /UsePrologue false /ColorSettingsFile () /AlwaysEmbed [ true ] /NeverEmbed [ true ] /AntiAliasColorImages false /CropColorImages false /ColorImageMinResolution 300 /ColorImageMinResolutionPolicy /OK /DownsampleColorImages false /ColorImageDownsampleType /Average /ColorImageResolution 300 /ColorImageDepth -1 /ColorImageMinDownsampleDepth 1 /ColorImageDownsampleThreshold 1.50000 /EncodeColorImages false /ColorImageFilter /DCTEncode /AutoFilterColorImages true /ColorImageAutoFilterStrategy /JPEG /ColorACSImageDict << /QFactor 0.76 /HSamples [2 1 1 2] /VSamples [2 1 1 2] >> /ColorImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000ColorACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000ColorImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasGrayImages false /CropGrayImages false /GrayImageMinResolution 300 /GrayImageMinResolutionPolicy /OK /DownsampleGrayImages false /GrayImageDownsampleType /Average /GrayImageResolution 300 /GrayImageDepth -1 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages false /GrayImageFilter /DCTEncode /AutoFilterGrayImages true /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict << /QFactor 0.76 /HSamples [2 1 1 2] /VSamples [2 1 1 2] >> /GrayImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000GrayACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000GrayImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasMonoImages false /CropMonoImages false /MonoImageMinResolution 1200 /MonoImageMinResolutionPolicy /OK /DownsampleMonoImages false /MonoImageDownsampleType /Average /MonoImageResolution 300 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages false /MonoImageFilter /FlateEncode /MonoImageDict << /K -1 >> /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile () /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False /CreateJDFFile false /Description << /ENU ([Based on 'No Compression'] [Based on 'No Compression wbleeed'] [Based on '[High Quality Print]'] Use these settings to create Adobe PDF documents for quality printing on desktop printers and proofers. 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