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Theriogenology 71 (2009) 13431357 www.theriojournal.com

Review

Compilation of classical and contemporary terminology used to describe morphological aspects of ovarian dynamics in cattle
A.T. Peter a,*, H. Levine b, M. Drost c, D.R. Bergfelt d
a

Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA b Tufts Ambulatory Service, Department of Environmental and Population Health, Cummings School of Veterinary Medicine, Tufts University, South Woodstock, CT 06267, USA c Department of Large Animal Clinical Sciences, University of Florida, Gainesville, FL 32605, USA d School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA Received 7 August 2008; accepted 20 December 2008

Abstract Veterinarians and scientists involved in applied and basic research in cattle require a lexicon of terms that is used uniformly so that diagnoses and inference of results between and among studies can be correctly interpreted and substantiated or negated and therapy and hypotheses can be formulated without unnecessary confusion and redundancy in treatments and experiments. This review provides a compilation of many of the classical and contemporary terms used in association with ovarian dynamics primarily during the estrous cycle in cattle, which can also apply to other reproductive states. While many classical terms used to describe healthy and diseased conditions associated with follicles and corpora lutea are still applicable today, there are some that have become antiquated (e.g., cystic corpus luteum, cystic ovarian degeneration, luteolysis, and granulosa cell tumor), due, in part, to advanced technology (e.g., ultrasonography) and a more thorough understanding of ovarian function. In this regard, older terms have been revised (e.g., corpus luteum with a cavity, follicular and luteinized-follicular cysts, structural and functional luteal regression, and granulosa-theca cell tumor) and newer terms have been coined (e.g., follicle deviation) and advocated herein. Dening and adopting terminology used in bovine reproduction that is clear, precise and understandable and available in a single source, is expected to make the exchange of clinical and research information and outcomes more effective, safe, and economical. Published by Elsevier Inc.
Keywords: Cattle; Terminology; Ovarian dynamics; Ovarian pathology

Contents 1. 2. Introduction . . . . . . . . . Estrous cycle. . . . . . . . . 2.1. Follicular phase . . 2.1.1. Proestrus . 2.1.2. Estrus . . . 2.2. Ovulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1344 1345 1346 1346 1346 1347

* Corresponding author. Tel.: +1 765 494 5808; fax: +1 765 496 1108. E-mail address: petera@purdue.edu (A.T. Peter). 0093-691X/$ see front matter. Published by Elsevier Inc. doi:10.1016/j.theriogenology.2008.12.026

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4. 5.

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Luteal phase . . . . . . . . . . . . . . . . . . . . . . 2.3.1. Metestrus. . . . . . . . . . . . . . . . . . . 2.3.2. Diestrus. . . . . . . . . . . . . . . . . . . . Follicular wave dynamics during the estrous cycle. 3.1. Follicular wave emergence . . . . . . . . . . . . 3.2. Follicle selection and deviation . . . . . . . . . 3.3. Follicle dominance . . . . . . . . . . . . . . . . . . Classication of anestrus . . . . . . . . . . . . . . . . . . Ovarian diseases . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Follicular and luteinized-follicular cysts . . . 5.2. Parovarian cysts . . . . . . . . . . . . . . . . . . . . 5.3. Fibrin tags . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Granulosa-theca cell tumor . . . . . . . . . . . . 5.5. Rete ovarii (ovarian cyst) . . . . . . . . . . . . . 5.6. Ovarian bursa adhesions . . . . . . . . . . . . . . 5.7. Ovarian hypoplasia . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Historically, terminology used to describe the reproductive tract in female cattle was based, in part, on gross examination in situ or ex situ during surgery or necropsy, respectively. In the 1980s, with the advent of ultrasonography and the ability to view structural changes of the bovine reproductive organs in a noninvasive manner over time [13], some of the original terms used to describe the reproductive tract required qualication or replacement and, in some instances, new terms were coined and advocated. However, modifying or replacing traditional or conventional terminology used in bovine reproduction with contemporary language is not always universally accepted; therefore, the scientic and lay literature and reference texts are lled with terms, denitions and colloquialisms that are often antiquated and ambiguous. Although reproductive disorders can be diagnosed in the clinic or in the eld [413], the diagnostician is not always the person doing the corrective surgery, therapy, or management. Cases are often transferred between or among veterinarians and staff and, therefore, records that contain terms that are out-dated and indenite can potentially result in misinterpretation of the original diagnosis and, consequently, animals may receive unintended treatment, which can be an economic loss to the producer and, perhaps a liability to the practitioner. Comprehensible and precise denitions are necessary for differential and accurate diagnoses of any disorder and for evaluating the benet-to-risk ratio,

as well as prognosis or effectiveness of corrective and therapeutic regimes [14]. Correspondingly, scientists involved in applied and basic research in cattle require a lexicon of terms that is used uniformly among individuals so that inference of the results between and among studies can be correctly substantiated or negated, and new hypotheses can be formulated without unnecessary redundancy in experiments. Thus, dening and adopting terminology used in bovine reproduction that is clear, precise and understandable is expected to make the exchange of clinical and research information and outcomes more effective, safe and economical. In 1976, a committee was convened and charged with making recommendations for standardizing terms used in bovine reproduction [15]. Although some of the proposed terminology may be out-dated, the nal report recommended nomenclature that covered fetal membranes, embryonic and perinatal periods, reproductive dysgenesis and normal development of the bovine conceptus. Over the last 20 years, numerous reports [1624] have become available that have dened healthy and diseased conditions pertaining to the principal organs (ovaries and uterus) of the bovine reproductive tract during various reproductive states, as well as rationale for correcting or managing the disorders; however, the terminology is scattered throughout the literature. There is no comprehensive report that has focused on compiling the various terms and denitions used to characterize normal and abnormal conditions associated with either the ovaries or uterus into a single source.

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The objective of this review is focused on the bovine ovary and is expected to be one of a series of reviews to summarize classical and current terminology that has been used to dene healthy and diseased conditions associated with follicular and luteal gland development in dairy and beef cattle, encompassing both Bos taurus and Bos indicus cattle, and primarily within the context of the estrous cycle. 2. Estrous cycle Although terminology associated with the bovine ovary will primarily be discussed in context with the estrous cycle, most terms are also applicable to pregnancy, post-partum and anestrus. Basic concepts and terminology of the bovine estrous cycle will be presented and summarized as previously reviewed [25] to provide a framework for the discussion of the various terms applied to ovarian dynamics during the cycle, as well as during other reproductive states. Terms used to describe the estrous cycle in cattle have slightly different meanings and spellings. The word estrous is an adjective used to describe the estrous cycle or some aspect of it (e.g., estrous behavior), whereas the word estrus is a noun indicating the period of sexual receptivity. In regard to the latter, the term heat is often used synonymously with estrus. In British and European literature, oestrous and oestrus are the preferred spellings, based on the Greek origin of the word oestrus; a family of biting insects (oestridae) that tormented cattle and induced a state of frenzy. Estrual is also an adjective

used to identify a condition related to estrus (e.g., estrual uid). European and Zebu breeds of cattle are generally considered seasonally polyestrus, which is dened as the repeated distribution of estrous cycles throughout the year. If the regularity of estrous cycles is interrupted by pregnancy and lactation or, perhaps, by improper nutrition, environmental stress or general and reproductive diseases, there is a period of anestrus (without cyclicity) or a condition of irregular estrous cycles. The clinical importance for identifying the basis of anestrus is discussed in detail in Section 4. It should be recognized that polyestrus and anestrus can also be used as adjectives (i.e., polyestrous and anestrous) preceding a noun (e.g., anestrous cow). Although puberty is generally dened as the lifestage where the female has attained the capacity to successfully produce offspring, the rst ovulation in the life of the animal marks the beginning of a rhythmic pattern of reproductive cyclicity. The basis for the estrous cycle is to provide females repeated opportunities to become pregnant, as each estrous cycle usually terminates with ovulation at the end of estrus. In general, the length of the estrous cycle in beef and dairy cattle ranges from 18 to 24 d [25], which is inuenced, in part, by the length of the luteal phase and number of follicular waves per cycle as discussed in Section 3. The length of the estrous cycle can be referenced from either the detection of estrus to detection of the next estrus (i.e., estrous cycle; Fig. 1) using visual observation or marking devices, or from detection of ovulation to detection of the next ovulation (i.e., interovulatory

Fig. 1. Terms and concepts related to stages within the follicular and luteal phases in association with respective changes in circulating concentrations of estradiol (E2), progesterone (P4) and preovulatory (OV) gonadotropin surge during the bovine estrous cycle. Adapted from [25] and reprinted with permission.

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Fig. 2. Terms and concepts related to follicular wave emergence (WE) and subsequent development of Wave 1 (anovulatory) and Wave 2 (ovulatory, OV) in association with respective FSH surges during the bovine estrous cycle. Adapted from [1] and reprinted with permission.

anywhere in-between (i.e., within approximately 24 h from the last examination). Furthermore, ovulation typically occurs approximately 1 d after estrus (approximately 29 h; [25]). Hence, by adjusting the data relative to estrus by 1 d so that Day 1 or Day 2 postestrus is equivalent to ovulation on Day 0, a more accurate assessment of the results between or among studies using different times of reference can be made. Physiologically and behaviorally, the estrous cycle consists of the follicular phase with proestrus and estrus, and the luteal phase with metestrus and diestrus, as previously described [25]. Morphological, physiological and endocrinological distinctions between the various stages of the follicular and luteal phases of the estrous cycle are summarized in the following sections. 2.1. Follicular phase The follicular phase is a relatively short period (approximately 20%) of the estrous cycle, from the beginning of regression of the corpus luteum to ovulation, that involves proestrus and estrus (Fig. 1). In general, the follicular phase is characterized by the onset of estrous behavior and a shift from progesterone dominance to estrogen dominance, primarily as a result of structural and functional regression of a mature corpus lutuem to a regressed corpus albicans (decreased progesterone) and development of a preovulatory follicle (increased estradiol) as depicted diagrammatically (Figs. 1 and 2). 2.1.1. Proestrus Proestrus (before estrus) is the initial portion of the follicular phase that begins with structural and functional regression of the corpus luteum and ends at the onset of estrus (Fig. 1). As the luteal gland regresses and circulating concentrations of progesterone decrease, there is an increase in estradiol that plays a role in the increase in uterine tone [26] and discharge of clear and watery mucus from the vulva [27]. Follicular dynamics during proestrus involve continued regression of the dominant follicle (Table 1) from the previous anovulatory wave that overlaps with growth of the dominant follicle of the ovulatory wave (Fig. 2). 2.1.2. Estrus Estrus is the latter portion of the follicular phase that ends with ovulation of the dominant follicle. Circulating concentrations of estradiol reach peak concentrations (Fig. 1) in association with the onset of sexual receptivity, as indicated by estrous behavior (heat)

interval; Fig. 2) using transrectal palpation or ultrasonography. In earlier studies, day of detection of estrus was often used as a point of reference designated Day 1 and, in later studies, especially with the use of ultrasonography [1], detection of ovulation has been preferred as a less variable and more distinctive event to serve as a point of reference, designated Day 0 as indicated in Figs. 1 and 2. Through palpation or ultrasonic imaging of the ovaries, ovulation is readily detectable and is the recommended point of reference that should be dened (i.e., Day 0 = ovulation) for communicating the number of days post-ovulation in non-pregnant as well as in pregnant animals [2]. In situations where transrectal palpation experience and ultrasound examinations are limited, the beginning of observed estrus may still be used as reference; however, it should be dened (e.g., Day 0 = rst detection of estrus), accordingly to avoid miscommunication of the timing of therapies or treatments and misinterpretation of study results. When making comparisons between or among studies that have used Day 0 or Day 1 relative to estrus and Day 0 relative to ovulation as the reference point, it may be necessary to adjust the data by 1 d so that an approximation can be made to the day of ovulation for a more accurate interpretation of the results. In general, the time of ovulation is dened as the disappearance of a dominant follicle that was present at one examination and gone the next, as determined by transrectal palpation or ultrasonography. Considering that examinations are done daily or at approximately 24-h intervals, ovulation could occur soon after the last examination, soon before the next examination or

A.T. Peter et al. / Theriogenology 71 (2009) 13431357 Table 1 Terms and concepts of ovarian follicles and corpora lutea associated with folliculogenesis and luteogenesis in cattle. Cohort of follicles Largest follicle

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Second, third, fourth, etc., largest follicles

Dominant follicle

Subordinate follicles Pre-ovulatory follicle Corpus luteum Corpus hemorrhagicum Corpus luteum with a cavity

Corpus albicans

A cohort of follicles is a group of antral follicles that constitute a follicular wave from rst detection at 14 mm in diameter within a 23 d interval. The largest follicle is the largest antral diameter follicle of the cohort of follicles of a wave before deviation and is sometimes referred to as the future dominant follicle, due to its propensity to maintain its hierarchal position within the cohort during the common growth phase and become the dominant follicle after deviation. The second, third, fourth, etc., largest follicles are the next largest follicles of the cohort of follicles of a wave before deviation and are sometimes referred to as future subordinate follicles, due to their propensity to maintain their hierarchal positions within the cohort during the common growth phase and become respective subordinate follicles after deviation. The dominant follicle is the largest antral follicle of the cohort of follicles of a wave after deviation that typically reaches 10 mm in diameter and includes co-dominant or multiple dominant follicles that can be ovulatory as well as anovulatory. The subordinate follicles are the next largest antral follicles of a wave after deviation that are typically <10 mm in diameter and are anovulatory. The pre-ovulatory follicle is the dominant follicle after deviation that is selected for nal maturation and ovulation (sometimes referred to as the Graaan follicle). The corpus luteum or luteal gland is formed at the site of the previous dominant follicle after ovulation, through the structural and functional transformation of theca and granulosa cells to luteal cells. Transient morphological characterization of a corpus luteum or luteal gland that is formed at the site of the previous dominant follicle immediately after ovulation that develops an intra-luteal blood-lled cavity. The term corpus luteum with cavity replaces the term cystic corpus luteum as a non-pathological luteal gland in which a distinct uid-lled cavity central to luteal tissue formation persists after the initial formation of a corpus hemorrhagicum. The corpus albicans is the remnant of the luteal gland following structural and functional regression of luteal cells.

and discharge of cohesive strands of mucus from the vulva. Final growth and maturation of the preovulatory follicle (Fig. 2) occurs in association with a decrease in estradiol concentrations and a preovulatory gonadotropin surge primarily involving LH and to a lesser extent FSH, which precedes ovulation by approximately 29 h [25]. Detection of mounting behavior associated with estrus (heat) is displayed by approximately 90% of cows [28] and is critical for determining the onset of standing estrus which is closely related to the timing of ovulation (e.g., approximately 29 h post-estrus). Standing estrus or standing heat with an arching of the back (standing to be mounted) is a mating posture termed lordosis, which characterizes the most denitive sign of estrus. Secondary signs of estrus may be indicative that sexual receptivity is approaching; however, they may occur before, during, or after estrus. They include, trailing, snifng the genitalia and attempts to mount other animals, mucus discharge and swelling and reddening of the vulva, and increased bellowing, restlessness, chin resting, and lip curling. Occasionally pregnant cows exhibit signs of estrus, usually during middle to late gestation. The terms silent estrus (silent heat) and silent ovulation are used to characterize the condition of

ovulation without estrus [29]. Silent heat is a condition that has been mostly associated with post-partum ovulations in lactating cows. The incidences of silent ovulation at the rst, second, third and fourth ovulations post-partum were reported to be 83, 46, 13, and 0%, respectively [30]. Some clinicians [31] prefer to classify silent ovulation as a type of anestrus termed subestrus in which the incidence has been reported to range from 34 to 50% [31,32]. However, since silent ovulation is associated with ovulation and not anovulation, it seems more appropriate to address silent ovulation as a separate condition apart from anestrus. 2.2. Ovulation Ovulation is the terminal event of estrus characterized by the rupture of a dominant follicle, evacuation of follicular uid, granulosa cells and oocyte, and early development or formation of a corpus luteum at the ovulation site. Although cattle are considered a monotocous species that typically ovulate a single dominant follicle, there is some degree of multiple spontaneous ovulations that appears to be inuenced by a variety of factors (e.g., breed, parity, nutrition, and reproductive status) [33]. In one study involving 1917

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high-yielding dairy cows [34], the double ovulation rate was 16%, with 52.7% unilateral (42.5% on the left ovary and 57.5% on the right ovary) and 41.5% bilateral ovulations. Furthermore, the triple ovulation rate was 5.8%. The incidence of synchronous (same day) versus asynchronous (>1 d apart) ovulations was not reported. 2.3. Luteal phase The luteal phase is the longer period of the estrous cycle, comprising approximately 80% of the cycle from ovulation to regression of the corpus luteum that involves metestrus and diestrus (Fig. 1). In general, the luteal phase is characterized by a shift from estrogen dominance to progesterone dominance [35] following ovulation (decreased estradiol), and structural and functional maturation of a corpus lutuem (increased progesterone). In association with the periodic emergence of follicular waves and corresponding FSH surges, there are also low-level uctuations (i.e., transient increases and decreases) in systemic concentrations of estradiol associated with follicular wave development throughout the luteal phase (Fig. 1). 2.3.1. Metestrus Metestrus is the immediate time after estrus or the initial portion of the luteal phase that begins at ovulation and ends at diestrus (Fig. 1). In this regard, metestrus is sometimes referred to as early diestrus, which extends to approximately 5 d after ovulation. At the ovarian level, metestrus involves luteinization of follicle cells of the previous dominant follicle into a corpus luteum (Table 1). Luteinization is a complex process that involves remodeling of stromal and vascular tissue and cellular and biochemical transformation of follicle androgen- (theca) and estrogen (granulosa)-producing cells into luteal progesterone-producing cells [36]. In cattle, early formation of the luteal gland is often associated with the formation of a transient intra-luteal blood-lled cavity resembling a blood clot; this structure is termed a corpus hemorrhagicum (Table 1) [25], which is comparable to the term used in horses [41]. Thereafter, as the bovine luteal gland completes its structural and functional transformation towards the end of metestrus, it becomes morphologically homogeneous, appearing as a uniform echodense structure upon detection with ultrasonography or appears heterogeneous with an anechoic uid-lled, intra-luteal cavity [1]. Regarding the latter, intra-luteal cavities in cattle can persist as uid-lled cavities after the initial stages of corpus hemorrhagicum formation and range in size from small (e.g., <2 mm) to large

(e.g., >10 mm), such that the larger the cavity the longer it is observed post-ovulation [3739]. The frequency of occurrence of one or the other morphologies (i.e., corpus luteum with or without a cavity) may be different between heifers and cows. In cows [37], the number of corpora lutea with a cavity versus without a cavity was 37% versus 63%, whereas, in heifers [38], the frequency was 79% versus 21%, respectively. Despite the apparent difference between cows and heifers in the occurrence of corpora lutea with and without a cavity, progesterone concentrations, interovulatory intervals and pregnancy rates were not affected by the different types of luteal gland morphologies in cows and heifers [37,38]. Historically, a corpus luteum with an intra-luteal cavity was referred to as a cystic corpus luteum which was considered a diseased or pathological condition [40]. However, considering there is no detectable difference in function (i.e., progesterone output) or fertility (i.e., estrous cycle length and pregnancy rate) between the two types of luteal gland morphologies, it is generally accepted that a corpus luteum with an intra-luteal cavity is not a pathological condition. The term cyst or cystic can be used anatomically in a pathological as well as a nonpathological manner. To avoid confusion between the terms luteal cyst, which is considered a diseased, morphological structure (see Section 5), and cystic corpus luteum, which is considered a healthy, morphological structure, the contemporary term corpus luteum with a cavity (Table 1) has been suggested to replace the classical term cystic corpus luteum [37]. In association with an increase in the progesteroneto-estrogen ratio during metestrus (Fig. 1), the endometrial epithelium is denuded [42], particularly in the intercaruncular areas [43], leading to the appearance of bloody mucus at the lips of the vulva. Metestrous bleeding is a process of diapedesis and is characterized by a discharge of bloody mucus from the vulva [43,44]. Metestrous bleeding is noticed 2448 h after estrus and is observed in 7590% of heifers and 4861% of cows [42], and its occurrence has no correlation with conception. Metestrus also encompasses some aspects of development of the rst anovulatory wave (Wave 1) of the estrous cycle (Fig. 2). 2.3.2. Diestrus Diestrus begins after metestrus and ends around the beginning of regression of the corpus luteum, near the time of proestrus (Fig. 1). The end of metestrus is characterized by cessation of metestrous bleeding, suppressed estrous behavior and a relatively mature

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corpus luteum, with increasing systemic concentrations of progesterone. Throughout diestrus, a mature corpus luteum maintains maximal concentrations of progesterone during emergence of Wave 2 (Fig. 2) and Wave 3 in two- or three-wave estrous cycles. In the absence of pregnancy, structural and functional regression of the corpus luteum occurs spontaneously primarily in response to uterine PGF2a during late diestrus [45]. Historically, the term luteolysis has been most commonly used to describe regression or lysis of the luteal gland. However, it appears to have a very limited meaning that no longer describes properly the complex sequence of synchronized molecular events that are now known to be associated with the demise of the corpus luteum. Contemporarily, therefore, luteal regression is the preferred terminology [46] that may be preceded by the terms functional and/or structural to clarify the context in which luteal regression is presented (i.e., endocrinologically or morphologically). Nonetheless, subsequent to diestrus, the corpus luteum regresses structurally (e.g., decrease in diameter) and functionally (e.g., decrease in progesterone) in non-pregnant animals to form a corpus albicans (Table 1) at the beginning of proestrus. 3. Follicular wave dynamics during the estrous cycle Follicular wave dynamics during the estrous cycle has been well described in cattle and recently reviewed [4749]. The follicular wave pattern depicted in Fig. 2 is that of a two-wave pattern; however, three-wave patterns are also common in cattle (>95% of the estrous cycles have two- or three-wave patterns), with one- and four-wave patterns being rare [50,51]. In general, development of a follicular wave involves the organized and simultaneous growth of a cohort (Table 1) of gonadotropin-dependent antral follicles (i.e., wave emergence) within a 23 d interval. The cohort of follicles associated with the wave initially increase in size during a common growth phase and subsequently differentiate into a single dominant follicle (Table 1) that continues growth, whereas multiple subordinate follicles (Table 1) cease growth during a static phase (i.e., deviation; Fig. 2). By the time the dominant anovulatory follicle of Wave 1 (and Wave 2 in three-wave estrous cycles) or the dominant ovulatory follicle of Wave 2 or Wave 3 reaches its static or preovulatory phase, corresponding subordinate follicles have committed to regression. Subsequent to deviation, morphological (i.e., size) and physiological/

endocrinological (i.e., FSH-suppressing capacity) dominance of the selected follicle is maintained for the remainder of the growth phase and mid-way through the static phase for anovulatory dominant follicles or until ovulation. Although the physiological/endocrinological dominance of the anovulatory follicle begins to wane during the static phase, morphological dominance is still apparent until regression to <10 mm (Fig. 2). In this regard, more than one examination (e.g., transrectal palpation or ultrasonography) is required to differentiate between a growing and regressing follicle. As a result of the loss of physiological/endocrinological dominance at ovulation, an FSH-surge precedes emergence of Wave 1 of the next cycle and, as a result of a similar loss of dominance during the static phase, an FSH-surge precedes emergence of Wave 2 in two-wave estrous cycles (Fig. 2) and Wave 3 in three-wave cycles. Studies using transrectal ultrasonography have characterized the composition and nature of follicular waves, and claried the morphological differences and timing of follicular events associated with multiple waves in prepubertal and adult cattle during the estrous cycle and pregnancy [1]. Breed, nutrition, parity and lactation are some of the factors that inuence the number of follicular waves per estrous cycle, number or cohort of follicles associated with a wave, and diameter of the largest or future dominant follicle at deviation, dominance and pre-ovulation. The endocrinology of follicular wave dynamics has been reviewed [49]; the most notable systemic hormonal change is an FSH surge that stimulates the emergence of each follicular wave during the estrous cycle (Fig. 2). The initial increase in FSH has been associated with follicles 13 mm in diameter [52], with peak concentrations occurring around the time the largest follicle of the wave reaches approximately 4 mm [1]. Thereafter, FSH concentrations progressively decrease, reaching basal concentrations during the late growth/early static phase of the dominant follicle. The next FSH surge and corresponding follicular wave soon follow. Discovery of the FSH surge-follicular wave interrelationship has led to subsequent discoveries on the nature of follicle selection (e.g., deviation) which have provided practical information for revising regimens for hormonal synchronization of estrous cycles used in breeding programs and timing of gonadotropin treatments used in embryo transfer programs [49]. For hypothesis testing, major aspects of follicular wave dynamics (i.e., emergence, deviation and dominance) have involved the sequential tracking of individual follicles to differentiate growing follicles of one wave from regressing follicles of a previous wave

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[53]. For practical purposes, the major aspects of follicular wave dynamics may be characterized by using a nonidentity method to sequentially monitor and determine the size of the three largest follicles within each ovary [1]. Morphological characteristics of follicular wave emergence, deviation and dominance associated with follicular wave dynamics have been recently reviewed [49] and are summarized in the next sections. 3.1. Follicular wave emergence Determining the day of wave emergence relative to ovulation on Day 0 can be done prospectively or retrospectively, according to when the largest follicle or dominant follicle, respectively, of the wave rst reaches a prescribed diameter [49,54]. Based on when the largest or dominant follicle of a wave rst reached 4 mm, emergence of Wave 1 (anovulatory) and Wave 2 (ovulatory) in two-wave estrous cycles occurred on approximately Days 0 and 10, respectively (Fig. 2), whereas emergence of Wave 1 (anovulatory), Wave 2 (anovulatory) and Wave 3 (ovulatory) in three-wave cycles occurred on approximately Days 0, 9 and 16, respectively. With advanced ultrasound technology, follicles 13 mm can be reliably and consistently detected [49]. Hence, the day of wave emergence would be expected to occur earlier (i.e., before ovulation) if follicles of the wave are rst detected at a smaller diameter [52]. Wave emergence is associated with a hierarchal arrangement of follicles, such that the largest follicle of the cohort usually maintains its position throughout the common growth phase and becomes the dominant follicle a majority of the time [54]. In this regard, the largest follicle is often referred to as the future dominant follicle (Table 1) and the next largest follicles as future subordinate follicles (Table 1) prior to deviation. The interrelationship between the length of the luteal phase and maximal diameter of dominant anovulatory follicles inuences the interwave interval (i.e., emergence of one wave to emergence of the next wave; Fig. 2) during the estrous cycle and, consequently, the length of the cycle. While the estrous cycle or interovulatory interval is signicantly longer in cattle with three- versus two-wave cycles (approximately 23 d versus 20 d, respectively) as a result of a signicantly longer luteal phase (approximately 19 d versus 16 d, respectively), the interwave intervals are shorter in cattle with three-wave cycles, in association with smaller dominant anovulatory and ovulatory follicles compared to cattle with two-wave cycles [1,50].

Notably, spontaneous or hormonally induced prolongation of the luteal phase has been associated with Type IV anestrus and is discussed in Section 4. 3.2. Follicle selection and deviation In general, follicle selection is a process where, in monotocous species, typically one follicle is selected from a cohort of growing follicles and becomes dominant, with continued growth to preovulatory size before regressing or ovulating (Fig. 2); the remaining follicles of the wave (i.e., subordinates) regress. The follicle selection process is often thought to be a single event associated with the differential change in growth rates between the largest and next largest follicles of a wave (i.e., follicle deviation). However, the selection process likely involves several morphological and physiological/endocrinological events, perhaps, beginning with the settlement of primordial germ cells within the early ovary of the embryo/fetus. Other events under the umbrella of the follicle selection process may include the timing of recruitment of primordial follicles from the resting pool, hierarchal arrangement in growth of preantral follicles, stage of development, and size of antral follicles at the time of wave emergence, and commitment of subordinate follicles to regression following the differential change in development (morphological, physiological and endocrinological) of the largest and next largest follicles of a wave [5565]. To distinguish the abrupt separation in growth between the dominant and largest subordinate follicles in individual animals [56] during the selection process from the gradual separation in the mean diameter proles averaged among animals [50], the term follicle deviation was coined to replace follicle divergence, respectively. The timing of follicle deviation within an animal can be determined subjectively by visual assessment of the diameter growth proles between the two largest follicles [62]. The point of departure, or the time of the differential or distinctive change in the diameter proles, represents follicle deviation. The visual approach was compared to a more objective approach using a segmented regression model in Bos taurus [53] and Bos indicus [64] cattle. There was no difference between the two methods in either species; hence, the visual approach was considered reliable and more practical. Thus, follicle deviation occurs approximately 2.5 d after wave emergence (i.e., largest follicle 4 mm) and represents a major and readily observable morphological event involved in the follicle selection process associated with ovulatory as well as anovulatory follicular waves in cattle.

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The morphological and physiological/endocrinological basis for follicle deviation has been reviewed in cattle [6570]. In general, after wave emergence and peak concentrations of FSH, the common growth phase of wave development is associated with the declining portion of the FSH surge. During this time, there are differential changes between the future dominant and subordinate follicles regarding local (e.g., IGF and IGF binding proteins) and systemic hormonal mechanisms that, in part, regulate the decrease in FSH concentrations [59,62]. By the end of the common growth phase, there is a differential change in growth rates between the future dominant and subordinate follicles (i.e., follicle deviation). The time of deviation in Bos taurus non-lactating dairy and beef cattle according to diameter of the largest follicle has been reported to be approximately 8 mm [33] and, in lactating Holstein cows, approximately 9 mm [33]. In Bos indicus cattle, deviation occurred when the largest follicle reached approximately 6 mm [64]. The differences among cattle with respect to the timing of follicle deviation according to follicle diameter provides practical information for scheduling gonadotropin treatments to avoid the potential confounding, suppressing effect of follicle dominance on development of multiple dominant follicles (i.e., superstimulation) and ovulations (superovulation) [49]. 3.3. Follicle dominance Subsequent to deviation, morphological dominance can be observed by the size of the dominant follicle, using transrectal palpation or B-mode ultrasonic imaging [1], physiologically by blood-ow using color-Doppler ultrasonic imaging [3], and endocrinologically by follicular-uid hormone concentrations using immunoassays [59]. Physiological/endocrinological dominance has been substantiated by the negative inuence the dominant follicle has on subordinate follicles of the extant wave and emergence of subsequent waves using follicle ablation and gonadotropin and follicular uid treatments [47,49,56,62]. In general, a dominant follicle has been dened by size when it reaches 10 mm [1,62]. Dominance could also be dened according to its size at the time of deviation or its ovulatory capacity to respond to an ovulatory stimulus, as reported in Bos taurus [71] and Bos indicus [72] cattle. Notably, multiple dominant follicles may be associated with a wave, whether they are spontaneous or gonadotropin-treatment induced. The maximum diameter of the dominant follicle of anovulatory and ovulatory waves is approximately 16 mm [56] in Bos taurus and 11 mm in Bos indicus [73]. The nature of

dominance represents both physiological (e.g., vascularity, granulosa cell LH receptors) and endocrinological (e.g., follicular uid estradiol and inhibin) aspects of the dominant follicle during its growing phase, that indirectly inuence the regression of subordinate follicles and suppression of subsequent wave emergence through suppression of FSH (Fig. 2). The sequence of events associated with periodic surges of FSH and corresponding follicular waves is repeated throughout the estrous cycle and even into pregnancy, as indicated by the continuous emergence of follicular waves during gestation [1]. The regularity of these events, however, may be interrupted by disease conditions associated with the ovaries, which are addressed in the next sections. 4. Classication of anestrus Anestrus is a broad term that indicates the lack of expression of estrus (or absence of estrous signs), despite a diligent estrus detection approach. Although absence of behavioral and physiological characteristics of estrus can fall under anestrus, a true anestrous condition is primarily characterized by anovulation. Historically, anestrus was broadly classied into physiological and pathological (clinical) types, with the following representing the pathological type: (1) inactive ovaries (i.e., minimal follicle development, anovulation and no corpus luteum development); (2) silent ovulation (i.e., ovulation without behavioral estrus); (3) ovarian hypofunction (i.e., persistent dominant follicle); (4) cystic ovarian degeneration (i.e., follicular or luteinized-follicular cyst); and (5) persistent corpus luteum (i.e., lack of luteal regression) [74]. Contemporarily, anestrus has been classied in a novel manner according to ovarian follicular and luteal dynamics [23]. As discussed in the previous section, follicular wave dynamics involves three main morphological events: (1) emergence, (2) deviation, and (3) dominance ending in anovulation or ovulation. Classication of anestrus or anovulation based on follicle characteristics at emergence, deviation and dominance provides for a rational diagnosis and treatment of the underlying diseased condition. It should be pointed out that silent ovulation (lack of overt signs of estrus) and unobserved estrus (poor estrus detection approach) can apparently increase the incidence of anestrus in a herd; however, they are not included in this classication since the former is behavioral and the latter is a management issue. Only true or organic forms of anestrus [75] are classied in this review. For discussion purposes, the etiologies of the following four types of anestrus are depicted diagrammatically (Fig. 3).

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Fig. 3. Schematic representation of types of anestrous conditions based on the morphology and physiology of ovarian follicles in cattle. Adapted from [83] and reprinted with permission.

Type I: Follicle growth proceeds to detection of antral follicles at wave emergence and to pre-deviation size (e.g., follicles <10 mm) but not to dominance (i.e., follicle 10 mm). Diagnosis is based on multiple transrectal ultrasound examinations indicating follicles <10 mm in diameter and no detectable corpus luteum. Hence, Type I anestrus corresponds to the earlier classication of anestrus due to relatively inactive ovaries according to reduced follicle growth [74]. Type II: Follicle deviation and dominance is attained but the dominant follicle of the ovulatory wave fails to ovulate and, instead, regresses. Diagnosis is based on multiple transrectal ultrasound examinations at 7-d intervals, indicating no detectable corpus luteum or follicular cyst [76,77]. Similarly, Type II anestrus also corresponds to the earlier classication of anestrus due to relatively inactive ovaries and failure of ovulation [74,77]. Type III: Follicle dominance is achieved, but the dominant follicle of the anovulatory or ovulatory wave fails to regress or ovulate at the expected time and remains at preovulatory size or increases in size to form a persistent dominant follicle [78,79]. Persistent dominant follicles may develop into a follicular cyst or become

luteinized to form luteinized-follicular cyst (i.e., cystic follicular degeneration; Section 5). These anovulatory structures may persist for an extended interval before eventually regressing. Depending on the functional status of these structures during their development, they may be associated with the suppressed emergence of another follicular wave. Diagnosis is based on the history and morphological characteristics of follicular and luteal dynamics. Hence, Type III anestrus corresponds to the earlier classications of anestrus due to ovarian hypofunction and cystic ovarian degeneration, COD [74]. The pathological nature of COD and discussed in more detail in Section 5. Type IV: Although estrus is exhibited and ovulation and formation of a corpus luteum occurs as usual, the luteal gland persists beyond the expected time of regression, resulting in anestrus or an extended interestrus or interovulatory interval. A contributing factor may be the absence of an estrogenic dominant follicle at the expected time of regression of the corpus luteum [23]. Elevated systemic estradiol concentrations associated with development of the dominant follicle reportedly lead to an increase in uterine estradiol receptors and up-regulation of uterine oxytocin receptors and,

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consequently, pulsatile release of PGF2a [45]. In regard to the latter, uterine infection [80] and related pyometra can prolong the life of a corpus luteum as a result of reduced uterine PGF2a production [81]. Parity, dystocia, puerperal disturbances, premature lactation, heat stress, and early resumption of ovarian cyclicity after calving are other factors that have been suggested to increase the persistence of a corpus luteum and prolongation of the luteal phase [82]. Diagnosis is based on the history and morphological characteristics of the ovaries and uterus. Type IV anestrus (i.e., lack of luteal regression) corresponds to the earlier description of anestrus due to a persistent corpus luteum [74]. Treatment options for these four types of anestrus conditions are beyond the scope of this discussion but have recently been reviewed [83]. 5. Ovarian diseases The ovaries play a key role in reproduction as the source of oocytes and steroid hormones. Estrogens and progestins are necessary for behavioral and physiological aspects associated with follicular development, ovulation, luteal gland formation, pregnancy maintenance, parturition and lactation. Impairment of the hormonal control of any of these reproductive events can lead to acute or chronic sterility or infertility issues. Although gross anatomical images of some of the ovarian conditions discussed in the next sections have been complied [84], a compilation of ultrasonographic images of diseased or pathological conditions of bovine ovaries is lacking. 5.1. Follicular and luteinized-follicular cysts Follicular and luteinized-follicular cysts are collectively referred to as abnormal structures associated with cystic ovarian degeneration or disease. As mentioned earlier (Type III anestrus), a follicular cyst arises from a persistent dominant follicle. Although the etiology is not thoroughly known, if left undiagnosed, the follicle cells (granulosa and theca) of the cyst begin to luteinize, such that they take on different structural and functional characteristics to become a luteinized-follicular cyst previously known as a luteal cyst [85]. A follicular cyst is dened as an anovulatory follicle-like structure [86] of the ovary which is uid-lled, usually >24 mm in diameter, which persists for more than 710 d in the absence of a corpus luteum [87]. In regard to the latter, the presence or absence of a corpus luteum as a component of the denition of a luteinized-follicular cyst is debatable [88]. In addition, the size of a luteinized-follicular cyst

may be <20 mm in experimentally induced cysts, particularly, if there is more than one [24]. Based on transrectal palpation, it has been established that follicular cysts are typically larger (>2 cm) than a preovulatory-sized follicle and have a feeling of being thin walled, uid-lled and easily ruptured during manipulation, whereas luteinized-follicular cysts have a rmer feel and are less fragile, due in part, to a wall of apparent luteal tissue. According to ultrasonographic morphology, both follicular and luteinized-follicular cysts appear as anechoic structures; however, the latter appears with a thicker wall of apparent luteal tissue [87] that can vary from an irregular pattern to a fairly welldened border [90,91]. Morphologically, luteinizedfollicular cysts may resemble corpora lutea with a cavity and, endocrinologically, circulating concentrations of progesterone are similar to concentrations during the expected luteal phase of the estrous cycle [92,93]. Although ultrasonography has provided a better understanding of the characteristics associated with gross development, diagnosis and differentiation between follicular and luteinized-follicular cysts, the etiology [85] and optimal regimens for treatment of the condition [87,89] are not thoroughly known. 5.2. Parovarian cysts Parovarian cysts are cystic structures near the ovaries in the broad ligament and close to the uterine tubes. They can be detected using transrectal palpation or ultrasonography as uid-lled, anechoic structures and are usually round or oval in shape, occur as a single cystic structure, and range from 15 cm in diameter. The relatively larger paraovarian cysts are referred to as hydatid of Morgagni, similar to those observed in ewes and sows [94,95]. Paraovarian cysts are vestiges of the mesonephric (Wolfan) or paramesonephric (Mullerian) duct systems and are of two types. Cysts derived from the cranial mesonephric tubules are referred to as epoophoron, whereas those derived from the caudal mesonephric tubules are referred to as paroophoron. Paraovarian cysts are considered morphologically and physiologically benign; they have no apparent effect on the estrous cycle and fertility [96]. 5.3. Fibrin tags Small tags of brin, particularly in heifers, from bleeding after ovulation are frequently attached to the ovary at the site of a previous ovulation or on the medial attachment of the ovary to the uteroovarian ligament and are commonly referred to as ovulation tags. There is

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a paucity of information about these tags, but it appears that they do not interfere with subsequent ovulations or conceptions [96]. 5.4. Granulosa-theca cell tumor While granulosa cell tumor has been the classic terminology, granulosa-theca cell tumor is the preferred terminology since it appears both types of follicle cells are involved in the disease. Even though granulosatheca cell tumors are the most common ovarian tumors in cattle, they are rare (<0.5%). This type of tumor arises from the sex cord stromal tissue within the ovary and may be relatively small, solid, and yellow to white or large, lled with cysts of varying sizes and weigh 11.912.3 kg [96]. They are usually benign (no metastasis) but can be malignant and are often hormonally active. If undiagnosed or diagnosed and left intact, clinical signs progress through various stages beginning with nymphomania and ending with virilism. In some instances, mammary development is observed [97]. Diagnosis is based on clinical signs and transrectal palpation and ultrasound examinations [86]. Clinically, granulosa-theca cell tumors may be characterized by abnormal estrous cycles and follicular and luteal inactivity on the contralateral ovary. In the mare, granulosa-theca cell tumors are also differentiated by assay of circulating concentrations of androgens and inhibin [98], which apparently have not been fully characterized as diagnostic tools for granulosa-theca cell tumors in cattle. 5.5. Rete ovarii (ovarian cyst) In the hilus region of a mature ovary, the rete ovarii is found as a network arrangement of medullary tubules or cords near the mesoovarium. The cords are lined with cuboidal and columnar epithelium that differentiate to form granulosa-like cells possessing secretory activity [99]. Cysts associated with rete ovarii are not commonly linked to severe pathological lesions [100,101]; however, if the rete ovarii has a space occupying lesion, ovarian function may be jeopardized. Transrectal ultrasonic imaging of the reproductive tract has provided a tool for diagnosing and differentiating rete ovarii from other structures associated with the ovary. 5.6. Ovarian bursa adhesions

the uterine tubes. Historically, adhesions have been associated with physical rupture of a large cyst or expression of a corpus luteum. Fortunately, these antiquated procedures are no longer commonly practiced. Contemporarily, uterine irrigation with irritating uids in large volumes for therapeutic and non-therapeutic reason may leak into the bursa area and provoke an inammatory response. Notably, intensive and repeated handling of the reproductive organs involved in extensive reproductive programs may induce microscopic lesions on the peritoneal surface. In one instance involving 50% of the cows, lesions were present in the uterine tubes and adjacent tissues. These strands were made up of numerous laments, probably of collagen, and most likely correspond to the organized peritoneal brinous exudate that forms during peritonitis [102]. Adhesions between the mesosalpinx and mesoovarium often include the mbria and ovary and may be mild, consisting of a few brous strands, moderate with more than a few strands but not enough to interfere with ovulation, or extensive to the point of concealing the ovaries which can interfere with ovulation. In extreme cases, adhesions may extend to the opening of the ovarian bursa, resulting in a very narrow opening that may affect fertility [103]. This condition is referred to as perisalpingitis and is rare [104]. Diagnosis is based on reproductive history and previous therapy for reproductive disorders combined with detailed and methodical transrectal and ultrasonographic examination of the reproductive tract. 5.7. Ovarian hypoplasia The hypoplastic ovary undergoes incomplete development (ovarian dysgenesis), such that the ovary lacks its usual full complement of primordial follicles. Hypoplasia can be unilateral or bilateral and can be partial or complete. Historically, this condition has been observed and documented in certain breeds of dairy and beef cattle. In heifers, hypoplastic ovaries may be small such that they are difcult to locate by transrectal palpation. The ovaries may feel like thin, narrow, rm cord-like structures. Lack of estrus associated with this condition has to be differentiated from anestrous conditions associated with other ovarian disorders previously discussed. Diagnosis is primarily based on transrectal examination. 6. Summary

A perivoarian adhesion usually results from ovarian trauma or peritonitis that may lead to blockage of ovum transport from the ovaries and embryo migration through

As one of a potential series of reviews, this review has focused on compiling many of the classical and current

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terms used to dene healthy and diseased conditions of the bovine ovary primarily during the estrous cycle. Although some classical terms associated with follicular and luteal gland development are still relevant today, other terms are antiquated (e.g., cystic corpus luteum, cystic ovarian degeneration, luteolysis, granulosa cell tumor) and are advocated herein to be replaced with more cotemporary terms (e.g., corpus luteum with a cavity, follicular and luteinized-follicular cysts, structural and functional luteal regression, granulosa-theca cell tumor). By compiling many classical and contemporary terms associated with ovarian dynamics in cattle into a single source that is clear, precise and understandable, it is expected that this review will make the exchange of clinical and research information and outcomes more effective, safe and economical. Acknowledgements In thanks and in memory of Howard Levine whose dedication and knowledge of bovine reproduction initiated the processes leading to this review. The authors also thank the following members of the American College of Theriogenologists for their valuable assistance in reviewing and contributing their knowledge in bovine reproduction to this effort: Gregg Adams, Louis Archbald, Lionel Dawson, Donald Schlafer and William Thatcher. References
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