Intraovarian spatial and vascular harmony between follicles and corpus luteum in monovulatory heifers, mares, and women

Accepted Manuscript Intraovarian spatial and vascular harmony between follicles and corpus luteum in monovulatory heifers, mares, and women O.J. Ginther PII:

S0093-691X(18)30859-8

DOI:

https://doi.org/10.1016/j.theriogenology.2019.01.019

Reference:

THE 14849

To appear in:

Theriogenology

Received Date: 25 September 2018 Revised Date:

18 January 2019

Accepted Date: 24 January 2019

Please cite this article as: Ginther OJ, Intraovarian spatial and vascular harmony between follicles and corpus luteum in monovulatory heifers, mares, and women, Theriogenology (2019), doi: https:// doi.org/10.1016/j.theriogenology.2019.01.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Revision to Theriogenology on Jan 18, 2019

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Review

Revised

Intraovarian spatial and vascular harmony between follicles and corpus luteum in

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monovulatory heifers, mares, and women

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O. J. Ginthera,b*

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aEutheria Foundation, Cross Plains, Wisconsin, USA

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b Department of Pathobiological Sciences, School of Veterinary Medicine, University of

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Wisconsin-Madison, Madison, Wisconsin, USA

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*Correspondence: Tel.: +1 608 798 4026.

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E-mail address: [email protected] (O.J. Ginther)

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Abstract

16 Heifers have two or three major follicular waves per interovulatory interval (IOI). In

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mares and women, the ovulatory wave is the only major wave in most (75%) IOI. The beginning

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of diameter deviation during follicle selection of the future dominant follicle (DF) is followed by

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continued growth of DF and decreasing growth of the future subordinate follicles. Diameter

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deviation in Bos taurus heifers, mares, and women begins when the future DF is a mean of 8.5,

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22.5, and 10.5 mm, respectively. Selection of the ovulatory follicle occurs more frequently from

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right ovary (RO) in heifers and women and from left ovary (LO) in nulliparous mares with no

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difference between ovaries in parous mares. The RO predilection for ovulation is preceded by a

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predilection for more follicles in RO before the beginning of deviation as indicated by (1) in

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heifers and women, there were more predeviation follicles in RO than LO and ovulation

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occurred more frequently from RO whereas in mares there was no difference between ovaries in

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number of predeviation follicles and ovulation occurred with similar frequency between ovaries

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and (2) in heifers, the number of ovulatory waves with DF in the ovary that had more

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predeviation follicles was greater than the number of waves with DF in the ovary that had fewer

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follicles. In heifers, ovulation from RO occurs more frequently when the regressed CL is also in

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RO and is attributable to a positive intraovarian effect of the CL on predeviation follicles that

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were adjacent to the CL. The positive two-way effect between CL and future DF when adjacent

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is expressed by greater dimensions and vascular perfusion of CL and DF. This phenomenon

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awaits study in mares and women. An exception to more frequent RO ovulation in heifers occurs

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in wave 3 owing to a switch during predeviation in future dominance to a smaller follicle when

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the largest follicle is adjacent to the regressing CL. A preovulatory contralateral relationship (DF

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ACCEPTED MANUSCRIPT 2 and CL in opposite ovaries) during the last wave of an IOI in heifers usually (eg, 88%) converts

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to an ipsilateral relationship during wave 1 of the next IOI in association with continuity in

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vascular perfusion and number of predeviation follicles per ovary. Alternating relationships

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between consecutive ovulations were not found in mares and is controversial in women. Applied

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potential of ovarian asymmetry is indicated by greater blastocyst rate for RO oocytes in cattle

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and greater pregnancy rate for RO ovulation in women.

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Keywords: Dominant follicle; Follicle selection; Follicular waves; Monovulatory species; Side of

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ovulation.

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1. Introduction

50 The abbreviations or acronyms that are used in text, tables, and figures of this review are

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listed (Table 1). Terminology is illustrated (Fig. 1) for follicle diameter deviation, switching in

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follicle destiny during luteolysis in ovulatory wave 3 in heifers so that the smaller follicle

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becomes the DF, DF-to-CL intraovarian patterns, and ipsilateral and contralateral relationships.

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The DF becomes the PF in the last wave of an IOI. Nomenclature used for intraovarian patterns

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and relationships between DF (or PF) and CL relationships are shown (Fig. 1, lower panel). A

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slant bar is used to indicate both pattern and side (eg, PF−CL/RO).

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The dynamics of follicular waves are considered and illustrated (Fig 1) before discussing

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intraovarian spatial harmony between follicles and CL and the RO predilection for ovulation. In

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heifers, mares, and women, a major follicular wave develops a DF, and each wave is generated

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by an FSH surge [1]. Minor waves are also generated by FSH but by definition do not develop a

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DF in heifers [2], mares [3], and women [4]. Minor waves will not be considered in this review.

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Two or three major waves occur during the IOI in cattle [5]. Wave 1 (first wave of the IOI) and

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wave 2 of three-wave IOI are anovulatory. Wave 2 in two-wave IOI and wave 3 in three-wave

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IOI are ovulatory. Wave 1 in cattle begins about 3 days before ovulation as 1- to 2-mm antral

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follicles during the end of the last wave of the previous IOI [6,7]. The follicles of waves 1, 2, and

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3 attain 4 or 5 mm by Days 0, 10, and 16, respectively [8]. Horses and humans have only the

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ovulatory major wave in 75% of IOI and the ovulatory wave and a preceding major anovulatory

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wave in 25% [9]. Growth rate of the future DF in the three species continues and the growth rate

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of subordinate follicles begins to wane in a process termed diameter deviation (Fig. 1) (reviewed

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in [10]). Deviation is a manifestation of follicle selection and begins when F1 reaches about 8.5,

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22.5, and 10.5 mm in heifers, mares, and women, respectively [11].

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Previous reviews have considered (1) the longtime mystery of selection of a DF from the many follicles of a follicular wave in cattle [10], horses [12], women [13], and the three species

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[14]; (2) an FSH-driven predeviation mechanism that spontaneously switches the apparent

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destiny of future dominance from a larger to a smaller follicle during the luteal phase in

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monovulatory species (cattle, horses, humans) [11]; and (3) functional asymmetries of the

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reproductive tract in cows [15,16] and mares [17]. This review considers intraovarian

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mechanisms that have been described primarily in cattle in the past 6 years including recent

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findings on the association between number of predeviation follicles per ovary and RO vs LO

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ovulation (Section 3), frequency of DF and CL in RO (Section 4), effect of a DF-to-CL

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relationship (DF and CL in same vs opposite ovaries) in a wave on the relationship in the next

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wave (Section 5), switching of follicle destiny in ovulatory wave 3 of three-wave IOI during

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luteolysis (Section 6), and two-way positive coupling between an adjacent DF and CL during

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predeviation in waves 1 and 2 (Section 7).

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Despite a complex but harmonious intraovarian interplay between follicles and CL,

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current management programs indicate that the ovaries are the most highly manipulated organs

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in the body especially in cattle but includes to a lesser extent other farm species and humans.

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These programs or techniques include (1) inducing luteolysis; (2) stimulating ovulation; (3)

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presetting the day of ovulation in an individual and synchronizing ovulations among individuals;

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(4) inducing multiple ovulations for embryo transfer purposes; and (5) collecting oocytes for

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maturation, fertilization, and embryo transfer. These manipulative programs are practical and

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efficient, but developers and operators should consider or at least appreciate the functional

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harmony among structures that has evolved within each member of this pair of relatively small

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organs.

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2. Functional ovarian asymmetries

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Ovulation in cattle occurs more frequently from the RO than LO (eg, 60% vs 40%) [18].

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The greater frequency of ovulation from RO was reported in cattle more than 100 years ago

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(cited in [15]) but the underlying mechanism involved has received basic research consideration

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only in the past several years. Although reports may be inconsistent, the RO is apparently more

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active also in goats, hamsters, humans, mice, rats, and sheep (reviewed in [18]). The RO

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predilection for ovulation in many mammalian species indicates that it is a fundamental

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phenomenon. Subsequent sections consider the asymmetries in ovulation frequencies and in

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number of follicles during the common growth phase (Section 3) and in types of intraovarian

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patterns (Sections 4, 5). Differences in physiologic events between sides may be a direct

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consequence of morphologic differences that were established during the fetal stage. In female

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calves in the first few weeks of life, the RO compared to the LO had significantly greater fluid

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volume for follicles 4 to 13 mm and greater weight [19]. This important finding has been almost

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dormant since 1935. No reports were found on differences in follicle dynamics between LO and

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RO for the bovine fetus or newborn calf. The RO predilection for ovulation is expressed at the

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first ovulation of sexual maturity [20]. In humans, the right fetal gonad is more developed than

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the left gonad as indicated by weight, protein content, and DNA content [21].

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Greater response of RO to superovulation treatment [22] and greater cleavage and blastocyst rates for RO oocytes have been reported in cattle [18]. Blastocysts formed from 42%

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of 697 bovine oocytes from RO and 21% of 523 oocytes from LO. This finding needs further

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study owing to potential applied as well as basic ramifications. Greater pregnancy rate from RO

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ovulation has been reported in women [23] but side differences were not detected in cattle

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[18,24]. Contrary to greater pregnancy rate from RO ovulation, an earlier report indicated that in

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lactating Holstein cows (n = 104) pregnancy rate tended to be greater (P < 0.08) when ovulation

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occurred from LO [25]. In a recent report in Holstein heifers (n > 1000 ovulations), pregnancy

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rate at 60 days was significantly greater when the PF was in LO [26]. Also, pregnancy rate was

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lower in heifers and cows when the DF-to-CL relationship of wave 1 was ipsilateral (DF−CL

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pattern) than when contralateral [27]. Further study will be required to unravel the factors

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involved in the greater pregnancy rate when PF is in LO and when the DF-to-CL relationship in

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wave 1 is contralateral. Reportedly, more female embryos develop from in vitro fertilized

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oocytes from LO than RO in cattle [28], and more female calves develop in the left horn and

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more male calves in the right horn [28,29]. The role of ovaries, oviducts, and uterus in gender

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differences between sides in cattle needs confirmation and further study. In cattle and rodents,

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the side of origin of the oocyte may determine the greater frequency of male and female

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offspring from RO and LO ovulations, respectively (reviewed in [18,28]).

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3. Relationship of number of predeviation follicles per ovary to ovulation

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asymmetry

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Heifers. A greater number of follicles develop in the RO of cattle during the IOI [30,31]. Studies in cattle [30,32] and sheep [33−35] prior to 2014 indicated that the CL had a positive

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intraovarian relationship to the number of follicles per ovary. A subsequent factorial study in

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heifers found that prior to deviation the RO and presence of the future DF but not the CL had a

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positive local association with number of follicles that attained at least 5 and 6 mm even after the

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future DF was excluded in the tally [36]. The local relationship between number of growing

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follicles and CL in previous reports was attributable to one-way analyses and the frequent

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occurrence of the CL in the same ovary as the DF. The positive relationships among number of

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follicles, RO, and the ovary containing the future DF have been confirmed using intraovarian

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patterns; more predeviation follicles occurred in RO when the RO later developed the DF

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(DF−CL/RO or DF/RO pattern/side) (Table 2) [37]. There was no significant difference between

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LO and RO when the ovary did not contain the DF (devoid pattern or CL pattern). The RO of

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ovulatory wave 2 is more likely to have more 6-mm growing follicles before deviation and

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therefore the PF is more likely to be selected from RO [38]. These studies have shown (1) the

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number of 6-mm predeviation follicles is greater for the RO and for the ovary that later

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developed the PF and (2) the number of ovulatory waves with the PF in the ovary that had more

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predeviation follicles is greater than the number of waves with the PF in the ovary that had fewer

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follicles [38].

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Mares. In a study of 21 middle-aged mares, there was no indication that number of

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predeviation follicles per ovary was related to side of ovulation, PF-to-CL relationship, or

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intraovarian pattern [39].

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Women. In pairs of ovaries with 2.0-to-10.0-mm follicles (presumably before deviation [9], an average of 1.2 more follicles were detected in RO than in LO [40]. Stimulation of follicles

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with FSH for IVF purposes, resulted in collection of significantly more oocytes from RO than

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from LO [41] and is consistent with more follicles in RO. These reports did not consider the

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intraovarian effect of the PF. Conclusion. In heifers, the RO and presence of the future DF but not the CL have a

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positive association with number of follicles in RO during the common growth phase. In women,

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more 2 to 10 mm follicles were detected in the RO apparently before deviation. In contrast, no

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differences between RO and LO in number of follicles were found in middle-aged mares. More

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follicles in RO during the common growth phase in heifers and women but not in mares matches

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the species that do and do not have a greater frequency of ovulation from RO.

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4. Side of ovulation and intraovarian patterns

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Heifers. The PF−CL pattern of the ovulatory wave in each of two-wave and three-wave IOI is more frequent in RO than LO (Table 3) [38,42] at both the beginning and end of IOI. That

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is, ovulation is more frequent in RO only when the regressed CL is also present in RO. The side

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of the future PF or selection of the ovulatory follicle is established by the end of the deviation

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process. That is, the formation of the PF−CL pattern develops during the common growth phase

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and is manifested after the beginning of diameter deviation. The greater frequency of the PF−CL

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pattern likely represents a two-way positive coupling between CL and future PF when they are in

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the same ovary and adjacent (Section 7). During Days 0 to 2, the mean growth rate is greater for

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most follicles that are adjacent to the CL. On day of deviation, the antrum of the future DF is

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closer to the CL wall than for the future largest subordinate. The positive effect of CL on

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ACCEPTED MANUSCRIPT 9 adjacent follicles contributes to the likelihood that the largest follicle (future PF) will develop in

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the ovary with CL. This is more likely to occur in RO owing to the RO predilection for more

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predeviation follicles (Section 3) on the side of the CL (dictated by side of the ovulation at

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beginning of IOI) and side of PF at end of IOI. In contrast to the greater frequency of the PF−CL

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pattern (ipsilateral relationship), a difference in frequency between RO and LO for the PF pattern

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(contralateral relationship) was not detected in either ovulatory wave 2 (two-wave IOI) or

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ovulatory wave 3 (three-wave IOI) (Table 3).

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Another phenomenon is also displayed in Table 3 as indicated by a greater frequency of the PF pattern (contralateral relationship) than the PF−CL pattern (ipsilateral relationship) in

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wave 3 but not in wave 2. This is a complication in studies of side of ovulation and is attributable

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to a switch in destiny for dominance from the larger follicle to a smaller follicle during the

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synchrony between the common growth phase and luteolysis in wave 3 by a mechanism that is

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discussed in Section 6. In ovulatory wave 2 of heifers, the greater frequency of RO ovulation

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involves a greater number of follicles (section 3) and more frequent development of the PF−CL

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pattern in RO during predeviation. These factors underlie the predilection for RO ovulation (Fig.

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2). Switching of the side of future PF from the side of the regressing CL can be to the opposite

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ovary and thereby would change the relationships between number of follicles and side of PF

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that were described for ovulatory wave 2. The reports that ovulation frequency is greater for RO

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are from averaging many observations that included both ovulatory waves 2 and 3. That is, the

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complexities of the PF−CL vs PF patterns in ovulatory waves 3 as a consequence of switching

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were masked by the pooling of two-and three-wave IOI.

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Studies in cattle on the physical interrelationships between follicles and CL did not find support for an effect of side on (1) differences in vascular perfusion during the conversion in

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intraovarian patterns between the preovulatory and postovulatory periods (Section 5), (2) two-

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way effects between DF and CL when adjacent in the DF−CL ovary (Section 7), and (3)

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variations in the follicle diameter characteristics of deviation [43]. Mares. In a survey totaled for 13 reports (9048 observations), ovulation occurred

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significantly more frequently from LO (53%) than from RO (47%) [44]. In a subsequent study,

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mares that were young and had not been pregnant previously had a greater ovulation frequency

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from LO (n = 122; 61%) than RO (79; 39%) [17]; mares that had been pregnant did not differ in

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ovulation frequencies between LO (922; 52%) and RO (867; 48%). The reason for loss of

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ovulation asymmetry after pregnancy is not known. Speculatively, the hypertrophy of the

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vasculature in each ovary in association with the massive development of large follicles and

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luteal structures in this species on Days 40−180 of pregnancy [44] may negate the predilection

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for ovulation from LO. No reports were found which considered LO vs RO in the number of

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luteal structures during pregnancy. An association between ovarian pattern and side of ovulation

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was not found in middle-aged mares with an unknown history of previous pregnancies (Table 3)

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[42].

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Women. Greater frequency of ovulation from RO is well established in women (eg, 55%

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vs 45%) (reviewed in [23]). The side of ovulation was not affected by the presence or absence of

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the CL in the ovary with the PF in a study of 100 ovulations (unpublished).

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Conclusion. In heifers and women, ovulation is more frequent from RO whereas in adult

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mares ovulation frequency is similar between RO and LO. In heifers, the PF in ovulatory waves

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2 and 3 is more frequently in RO when the CL is present (PF−CL/RO pattern/side) than for the

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PF−CL/LO pattern side indicating that both the PF and CL are associated with an increase in

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frequency of ovulation in RO. During the common growth phase of wave 3, the largest follicle

ACCEPTED MANUSCRIPT 11 may regress when adjacent to the regressing CL, thereby increasing the frequency of the PF

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pattern and CL pattern (contralateral relationship). In mares and women, the side of ovulation is

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not affected by presence or absence of the CL. This may reflect the relatively longer interval

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from the completion of CL regression to ovulation (follicular phase) in mares and women than in

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heifers.

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5. Frequency of consecutive ipsilateral and contralateral relationships

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Heifers. It has been long known that averaged for all waves the DF is more likely to develop in the ovary with the CL (ipsilateral relationship) [45]. More recent studies have

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indicated that the DF-to-CL relationship is influenced by wave sequence and by number of

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waves per IOI. Combined for six reports [36,37,46−49], the frequency of the ipsilateral

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relationship (DF−CL pattern and devoid pattern) was significantly greater than contralateral

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relationship (DF pattern and CL pattern) during wave 1 (306 vs 231; 57% vs 43%). To illustrate

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differences among reports, a study with > 300 cattle found no differences in the frequency of

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ipsilateral vs contralateral relationships during wave 1 [27]. The frequencies of the two

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relationships in the combined six cited reports were similar for anovulatory and ovulatory wave 2

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(343 vs 334; 51% vs 49%), and the frequency of the contralateral relationship was significantly

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greater during ovulatory wave 3 (176 vs 90; 66% vs 34%). The greater frequency of the

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ipsilateral relationship in wave 1 is attributable at least in part to the greater frequency of the

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contralateral relationship in wave 3 of the previous IOI (Section 6). The percentage of heifers

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with each of the four possible relationship conversions from the preovulatory period of the

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previous IOI to postovulatory period of wave 1 and the associated intraovarian patterns are

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shown (Fig. 3). Most (88%) conversions in relationships from the ovulatory wave to wave 1 of

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the next IOI were reversals. An interpretation for involvement of both the continuity in vascular perfusion or

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angioarchitecture and number of predeviation follicles per ovary in the conversion of

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intraovarian patterns from preovulation to postovulation is illustrated (Fig 4) [49]. The

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angioarchitectural aspect assumes that the major arteries that supply the large preovulatory

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follicle carry over into postovulation to supply the developing CL. This is consistent with the

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depicted continuity between periods in the vascular perfusion index. The considerable

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vascularity of PF and the resulting postovulatory CL apparently extends to the surrounding tissue

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and is associated with more 2-mm (preovulatory) and 6-mm (postovulatory) follicles. More

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follicles in the preovulatory ovary and a CL from ovulation of the PF result in the DF−CL

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pattern of wave 1 and more predeviation follicles in an ovary increases the likelihood that the DF

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will be in that ovary (Section 3). The CL pattern in the contralateral preovulatory relationship is

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most likely to convert to a devoid postovulatory pattern owing to continuing decrease in vascular

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perfusion from the regressing CL. The decrease in vascular perfusion is associated with fewer 2-

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mm follicles preovulatory and 6-mm follicles postovulatory. That is, a postovulatory CL does

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not form owing to the previous absence of a PF, and the likelihood of the formation of a DF is

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diminished from fewer follicles resulting in a devoid pattern. In ovulatory wave 2 of two-wave

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IOI, the frequencies are similar between ipsilateral and contralateral relationships [50] apparently

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because wave 2 is not preceded by the vascular perfusion and follicle population of a

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preovulatory period.

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ACCEPTED MANUSCRIPT 13 Mares. A study of 485 consecutive ovulations did not find an effect of relationships and

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ovarian patterns of an ovulatory wave on the ovulatory wave of the next IOI (Table 3) [42]. It is

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not known whether a major anovulatory wave will influence the relationships in an adjacent

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ovulatory wave in individual mares with more than one major wave per IOI. Measurable

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repeatability in individuals between consecutive IOI does occur in length of the IOI, diameter of

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the preovulatory follicle on Days −3 to −1, number of follicles per wave, and circulating

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concentrations of FSH and LH during the ovulatory wave [51].

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Women. Ovulation occurred more often (87%) from alternate ovaries based on histologic dating of the CL and corpus albicans [52], and another report indicated that the side of

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consecutive ovulations may influence pregnancy rate [53]. Reports of ovulation from CL ovary

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(same as ovulation from same ovary at each end of IOI) have been inconsistent (reviewed in

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[54]). In another primate (monkeys), the sides of consecutive ovulations have been reported to

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occur randomly [55] and alternately [56]. In women, an unpublished study indicated that side of

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two consecutive ovulations was available in 50 IOI from records of individual follicles identified

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from day to day by transvaginal ultrasonic imaging [9]. There were no significant differences in

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frequencies between ipsilateral (52%) and contralateral (48%) relationships or in consecutive

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ovulations from the same (52%) vs alternate (48%) sides. A report on 286 pairs of consecutive

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ovulations in women concluded that the side of ovulation did not affect the subsequent side of

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ovulation [54].

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Conclusion. The DF-to-CL relationship or intraovarian patterns can affect the

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relationships and intraovarian patterns of a subsequent wave in species (eg, cattle) with multiple

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major waves in an IOI. Conversions of ovarian patterns between the ovulatory wave and the

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adjacent wave 1 are influenced by continuity in vascular perfusion and number of follicles per

ACCEPTED MANUSCRIPT 14 ovary. In species (eg, horses, humans) or individuals without a major anovulatory wave

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preceding the ovulatory wave, the relationship and ovarian patterns of an ovulatory wave do not

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influence the characteristics of the next ovulatory wave based on reports with large numbers of

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subjects.

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6. Switching. Negative one-way effect of regressing CL on adjacent follicles

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Deviation in heifers has been partitioned into classes depending on the diameter of F2

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when F1 is 8.5 mm (expected deviation). The classes are (1) conventional (F2 ≥ 7.0 mm), (2)

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undersized (F2 < 7.0 mm), and F1,F2 switched (two largest follicles switch in destiny to become

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the DF vs largest subordinate) [43]. Switching between the future F1 and F2 occurs during

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predeviation and the luteal phase (functional CL), and has been reported for heifers, mares, and

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women (reviewed in [11]). The largest follicle during the common growth phase that was

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destined to become DF loses its status and the second-largest follicle assumes favored status and

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becomes the DFs. The switching during the luteal phase occurs when the FSH surge is near the

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ending nadir and the largest follicle is unprepared to respond to the low FSH concentration. The

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largest follicle is replaced by the next largest follicle during a subsequent increase in FSH. This

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section concerns another form of switching that occurs in heifers when the common growth

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phase is in synchrony with the luteolysis during ovulatory wave 3.

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Heifers. Several studies relate to a reported greater frequency of a contralateral

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relationship in ovulatory wave 3 than in other waves [25,46,47,57−59]. The conclusion from

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these reports is that a switch in follicle destiny from future dominant to future subordinate in

ACCEPTED MANUSCRIPT 15 wave 3 occurred when the largest follicle during the common growth phase was adjacent to the

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regressing CL (Fig. 5) [60−62]. As a test, luteolysis was induced with prostaglandin F2α

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(PGF2α) during the common growth phase. The destiny of the largest follicle changed in 13 of

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36 waves from future dominant to future subordinate when the follicle to CL relationship was

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ipsilateral than when contralateral 0 of 19. Furthermore, the growth rate was reduced for many

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predeviation follicles that were adjacent to the regressing CL. These studies showed that the

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largest follicle often does not become the DF when adjacent to a regressing CL during the

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common growth phase. A smaller follicle becomes the DF in either ovary thereby accounting for

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an increase in the frequency of the contralateral relationship.

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Switching during luteolysis may account for the report in lactating cows that the CL was in the RO more often before induction of luteolysis by a PGF2α analog 50 to 60 days postpartum

333

[18]; but the induced ovulation was more often in LO. This may have represented switching from

334

RO to LO. In another species (monkeys), ovulation tends to occur contralaterally when the

335

follicular phase is shorter (eg, 14 days) and randomly when the follicular phase is longer [63]. It

336

is not known whether these observations involve predeviation switching during luteolysis. Mares and women. Switching of follicle destiny during luteolysis has not been

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considered in mares and women. Luteolysis and the common growth phase of the ovulatory

339

wave may be asynchronous in individual mares [64] and women [9] and would likely negate the

340

switching phenomenon during luteolysis in most individuals.

341

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338

Conclusion. The greater frequency of the contralateral relationship during wave 3 in

342

cattle is attributable to decreased blood flow to the largest follicle during the common growth

343

phase when adjacent to the regressing CL. Another follicle is therefore selected to become the

344

DF. The newly selected DF may be in either ovary thereby increasing the frequency of the

ACCEPTED MANUSCRIPT 16 345

contralateral relationship in wave 3. Further study may show that switching of future dominance

346

to a smaller follicle during luteolysis also occurs in species other than cattle depending on the

347

timing in an individual between the common growth phase and luteolysis.

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348 349 350

7. Positive intraovarian effect between an active CL and adjacent follicles

SC

351

Heifers. During the common growth phase and extending to postdeviation, dimensions of

353

the future DF and CL and percentage of each structure with blood-flow color-Doppler signals are

354

greater when the DF and CL are in the same ovary and especially when adjacent [50,65−68]. The

355

two-way positive coupling occurs in wave 1 and wave 2 (Fig. 6) [65]. The positive coupling

356

between PF and CL does not occur in wave 3 owing to CL regression during predeviation

357

(Section 6) [50]. Specific indications [50,68] on the positive effect of the developing CL on the

358

follicles in the common growth phase include (1) when F1 is 5.5 mm, follicles that are < 2 mm

359

distant from the CL are an average of 1-mm larger than follicles ≥ 2 mm distant from the CL, (2)

360

the future DF is closer to the CL than the future largest subordinate, and (3) a correlation

361

indicated that the larger follicles on Day 0 were closer to the CL [68]. Greater vascular perfusion

362

of the DF−CL ovary occurs when DF and CL are adjacent than when separated. The two-way

363

coupling is no longer detectable by the last few days of a two-wave IOI owing to luteal

364

regression [68]. However, greater vascular perfusion specifically for the PF wall occurs on Days

365

−2 and −1 when the regressed CL is in the same ovary than when the CL is in the opposite ovary

366

[68]. It appears that the enhanced function of the PF when in the ovary with regressing CL may

367

represent the local effect of the CL on the PF that was initiated at predeviation during the luteal

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ACCEPTED MANUSCRIPT 17 phase. In this regard, vascular perfusion on the day of breeding is greater in the wall of the PF in

369

heifers that become pregnant than in those that do not [69], and the vascular perfusion is

370

positively related to the success of IVF and embryo development [70]. The report in cows that a

371

CL in RO on Day 8 produced more progesterone than for a CL in LO [16] may be a reflection of

372

greater CL blood flow but location of the DF was not reported.

373

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It has been proposed [65] but not documented that the positive (this section) and negative effects (Section 6) between follicles and CL, represent functional angiocoupling wherein either

375

structure signals for an increase in blood flow (two-way positive effect between DF and CL) or a

376

decrease in blood flow (one-way negative effect of CL regression on adjacent predeviation

377

follicles). This proposal assumes that a common arterial branch internal or external to the ovary

378

supplies both structures. Although the intraovarian system of arterial branching apparently has

379

not been described for cattle, a drawing of the intraovarian arterial system in humans shows a

380

common intraovarian branch to the DF and adjacent CL [71]. An older speculation is that each

381

structure produces a substance (eg, progesterone, estrogen) that has a positive effect on the other

382

through diffusion or a venoarterial pathway [58,72]. However, functional angiocoupling seems a

383

more reasonable interpretation as indicated by the following: (1) the coupling of the DF and CL

384

operates in two directions, (2) the positive two-way coupling on DF occurs in wave 1 when the

385

CL is developing (Days 0 to 2) and also in wave 2 when the CL is mature, and (3) a positive two-

386

way effect during both the luteal phase and the one-way negative effect of a regressing CL on

387

adjacent follicles during luteolysis.

M AN U

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388

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374

Mares and women. Positive or negative functional coupling between DF and CL

389

apparently has not been considered in species other than cattle. However, a report in women

390

concluded that the CL has a negative effect on neighboring follicles during the mid- and late-

ACCEPTED MANUSCRIPT 18 391

luteal phases [73]. It was suggested that the CL of women secrets a factor that affects

392

neighboring follicles and is reviewed.

393

395

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394

8. Overall conclusions

396

The predilection of the RO for more follicles during the common growth phase in cattle

SC

397

and women (Section 3) underlies the greater RO frequency for selection of the DF in major

399

anovulatory waves and the PF in ovulatory waves (Section 4). In cattle, the number of ovulatory

400

waves with the PF in the ovary that has more ≥ 6-mm predeviation follicles is greater than the

401

number of waves with the PF in the ovary that has fewer follicles. In addition, the RO

402

predilection for ovulation in cattle utilizes a positive intraovarian effect for the PF−CL pattern;

403

ovulation from RO is more frequent than from LO only when RO contains the regressed CL. The

404

functional CL has a positive effect on adjacent follicles during predeviation and thereby

405

increases the likelihood that the largest follicle (future PF) will develop in the RO with the CL.

406

The RO predilection for ovulation may include more efficient intraovarian vascular perfusion in

407

association with more follicles during predeviation and may in turn have a favorable impact on

408

the growing follicles and oocytes from RO (Section 2) and on selection of the DF or PF (Section

409

3). A fetal origin of more follicles in RO than in LO is supported by research on fetal ovaries,

410

although limited. It is unlikely that RO predilection is established between birth and sexual

411

maturity or by differences in location of the ovaries to other abdominal organs considering its

412

occurrence in many species of farm and laboratory animals and women. Greater RO activity can

413

be altered by the complexities of spatial relationships between follicles and CL. In wave 3 in

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ACCEPTED MANUSCRIPT 19 cattle, selection of the future DF can switch between ovaries owing to close proximity of a

415

regressing CL to the largest predeviation follicle (Section 6). As a result, the frequency of the PF

416

pattern (contralateral relationship) increases and the frequency of ovulation from RO decreases.

417

Predilection of RO for number of predeviation follicles and for side of ovulation has

418

ramifications for applied research owing to the need for high-quality oocytes for efficient

419

fertilization rate in vivo and in vitro.

The impact of a major follicular wave on the next wave has been demonstrated in a

SC

420

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414

species (bovine) with consistent multiple major waves in each IOI (Section 5). Continuity in

422

number of follicles and the extent of vascular perfusion are involved in the greater frequency of

423

conversion of a contralateral relationship during the last wave of an IOI to an ipsilateral

424

relationship in wave 1. In species (horses, humans) that usually have only one major wave per

425

IOI, the ovulatory wave, an effect of one wave on another has not been convincingly

426

demonstrated.

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A preferred overall interpretation is that the phenomena described herein are more likely from spatial and vascular harmony between intraovarian structures rather than from local passage

429

of hormones or factors. Vascular relationships seem more likely for the interplay between CL

430

and adjacent follicles in cattle considering especially that local effects between CL and a follicle

431

are positive on both structures during predeviation in the luteal phase (Section 7) and negative on

432

the largest predeviation follicle during luteolysis (Section 6).

434 435

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Acknowledgments

ACCEPTED MANUSCRIPT 20 436 437

The author thanks the Eutheria Foundation for financial support and S.V. Dangudubiyyam for assistance with word processing and figure preparation.

438

440

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References

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2. Ginther OJ. An FSH booster surge for resurgence of the preovulatory follicle in heifers. Dom

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27. Miura R, Haneda S, Kayano M, Matsui M. Development of the first follicular wave dominant

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32. Matton P, Adelakoun V, Couture Y, Dufour JJ. Growth and replacement of the bovine ovarian follicles during the estrous cycle. J Anim Sci 1981;52:813–20. 33. Dufour J, Ginther OJ, Casida LE. Corpus luteum action on ovarian follicular development

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ACCEPTED MANUSCRIPT 24 36. Ginther OJ, Hoffman MM. Intraovarian effect of dominant follicle and corpus luteum on

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number of follicles during a follicular wave in heifers. Theriogenology 2014;82:169–75.

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37. Ginther OJ, Hoffman MM. Interactions of side (left and right ovary) with the number of

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follicles per ovary and with the intraovarian relationships between dominant follicle and

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38. Ginther OJ, Dangudubiyyam SV. Effect of number of 6-mm predeviation follicles and

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40. Jokubkiene L, Sladkevicius P, Valentin L. Number of antral follicles, ovarian volume, and vascular indices in asymptomatic women 20 to 39 years old as assessed by 3-dimensional

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sonography. J Ultrasound Med 2012;31:1635−49.

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41. Lan KC, Huang FJ, Lin YC, Kung FT, Lan TH, Chang SY. Significantly superior response in the right ovary compared with the left ovary after stimulation with follicle-stimulating

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hormone in a pituitary down-regulation regimen. Fertil Steril 2010;93:2269−73.

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luteum and preovulatory follicle in heifers. Theriogenology 2013;80:114–9.

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47. Ginther OJ, Bashir ST, Rakesh HB, Hoffman MM. Hormone concentrations temporally associated with contralateral and ipsilateral relationships between the CL and preovulatory

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follicle during the third follicular wave in heifers. Theriogenology 2013;80:738–47. 48. Ginther OJ, Rakesh HB, Hoffman MM. Complex interrelationships among corpus luteum,

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preovulatory follicle, number of follicular waves, and right or left ovaries in heifers.

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49. Ginther OJ, Siddiqui MAR, Baldrighi JM, Hoffman MM. Conversion of intraovarian patterns from preovulation to postovulation based on location of dominant follicle and corpus luteum

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in heifers. Theriogenology 2015;83:153–61.

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50. Ginther OJ, Siddiqui MAR, Baldrighi JM. Effects of conversion of follicular activity from wave 1 to wave 2 and proximity of wave 2 follicles to CL in heifers. Theriogenology

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2015;83:1241–8.

51. Jacob JC, Gastal EL, Gastal MO, Carvalho GR, Beg MA, Ginther OJ. Temporal relationships

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and repeatability of follicle diameters and hormone concentrations within individuals in

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mares. Reprod Dom Anim 2009;44:92–9.

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52. Gougeon A, Lefevre B. Histological evidence of alternating ovulation in women. J Reprod Fertil 1984;70:7−13.

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54. Check JH, Dietterich C, Houck MA. Ipsilateral versus contralateral ovary selection of

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dominant follicle in succeeding cycle. Obstet Gynecol 1991;77:247−49.

55. Clark JR, Dierschke DJ, Wolf RC. Hormonal regulation of ovarian folliculogenesis in rhesus monkeys. III. Atresia of the preovulatory follicle induced by exogenous steroids and

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56. Hodgen GD. The dominant ovarian follicle. Fertil Steril 1982;38:281−300.

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57. Ginther OJ, Bashir ST, Hoffman MM, Beg MA. Endocrinology of number of waves per

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preovulatory follicle in heifers. Dom Anim Endcrinol 2013;45:64–71.

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58. Ginther OJ, Santos VG, Mir RA, Beg MA. Progesterone concentration when the future

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luteolytic period and locations of the preovulatory follicle and CL in interovulatory intervals

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with two or three follicular waves in heifers. Theriogenology 2014;81:787–96.

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60. Ginther OJ, Baldrighi JM, Siddiqui MAR, Bashir ST, Rakesh HB. Mechanism for greater

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frequency of contralateral than ipsilateral relationships between corpus luteum and ovulatory

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follicle for wave 3 in heifers. Theriogenology 2016;85:361−7.

591 592

61. Siddiqui MAR, Ginther OJ. Switching of largest follicle from dominant to subordinate status when follicle and CL are in same ovary in heifers. Theriogenology 2014;82:259–65.

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62. Ginther OJ, Siddiqui MAR, Baldrighi JM, Hoffman MM. Intraovarian factors associated

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with switching of a future dominant follicle to a subordinate follicle during induced

595

luteolysis in heifers. Theriogenology 2015;83:786–96.

600 601 602 603 604 605 606

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64. Santos VG, Bettencourt EM, Ginther OJ. Hormonal, luteal, and follicular changes during initiation of persistent corpus luteum in mares. Theriogenology 2015;83:757–65.

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in the rhesus monkey. Fertil Steril 1973;24:715−21.

65. Ginther OJ, Siddiqui MAR, Baldrighi JM. Functional angiocoupling between follicles and adjacent corpus luteum in heifers. Theriogenology 2016;86:465−71.

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63. Wallach EE, Virutamasen P, Wright K. Menstrual cycle characteristics and side of ovulation

66. Dominques RR, Ginther OJ. Angiocoupling between the dominant follicle and corpus luteum during waves 1 and 2 in Bos taurus heifers. Theriogenology 2018;114:109−15. 67. Ginther OJ, Rakesh HB, Hoffman MM. Blood flow to follicles and CL during development of the periovulatory follicular wave in heifers. Theriogenology 2014;82:304−11.

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68. Ginther OJ, Siddiqui MAR, Baldrighi JM, Hoffman MM. Effect of intraovarian proximity between dominant follicle and corpus luteum on dimensions and blood flow of each structure

608

in heifers. Theriogenology 2014;82:875–83.

609

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69. Siddiqui MAR, Almamun M, Ginther OJ. Blood flow in the wall of the preovulatory follicle and its relationship to pregnancy establishment in heifers. Anim Reprod Sci

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2009;113:287−92.

612

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70. Siddiqui MAR, Gastal EL, Gastal MO, Almamun M, Beg MA, Ginther OJ. Relationship of

613

vascular perfusion of the wall of the preovulatory follicle to in vitro fertilization and embryo

614

development in heifers. Reproduction 2009;137:689−97.

615

71. Redmer DA, Reynolds LP. Angiogenesis in the ovary. J Reprod Fertil 1996;1:182−92.

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72. Fogwell RL, Lewis GS, Butcher RL, Inskeep EK. Effects of ovarian bisection on response to

617

intrafollicular injection of PGF2α and on follicular development in ewes. J Anim Sci

618

1977;45:328−35.

620

73. Fukuda M, Fukuda K, Andersen CY, Byskov AG. Does corpus luteum locally affect follicular growth negatively? Human Reprod 1997;12:1024−27.

621

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622

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623

ACCEPTED MANUSCRIPT 29 624

Table 1. Abbreviations used in text, tables, and figures.

625 BF = blood flow color-Doppler signals as a percentage of follicle wall or luteal tissue.

627

CL= corpus luteum (functional or regressed during preovulatory period).

628

Day 0 (uppercase D) = day of ovulation. day 0 (lowercase d) = for other references.

629

DF = dominant follicle. F1 and F2 = future and established DF and largest subordinate.

630

IOI = interovulatory interval. LO and RO = left and right ovaries.

631

PF = preovulatory follicle or DF during the ovulatory follicular wave.

SC

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626

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632 633

AC C

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634

ACCEPTED MANUSCRIPT

Table 2. Number of follicles in ovulatory wave 2 that

636

reached 6 mm in LO and RO for the four intraovarian

637

patterns in heifers.

638 639 640 641

LO

RO

DF−CL/Ipsilateral

2.0 ± 0.2

3.2 ± 0.4*

642

Devoid/Ipsilateral

1.3 ± 0.3

0.8 ± 0.2

643

DF/Contralateral

1.9 ± 0.2

3.1 ± 0.4*

644

CL/Contralateral

1.2 ± 0.2

1.7 ± 0.4

645

649 650

Adapted from [38] with permission.

TE D

648

different (P < 0.05).

EP

647

An asterisk (*) indicates that the two means are

AC C

646

M AN U

Pattern/Relationship

SC

635

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30

ACCEPTED MANUSCRIPT 31 Table 3. Effect of PF-to-CL relationship, intraovarian pattern, and side (LO and RO)

652

on number and frequency of ovulation (Ov.) as indicated by side of preovulatory

653

follicle (PF) in heifers and middle-aged mares.

Heifers Two waves

Three waves

PF−CL/Ipsilateral

LO

52 (35%)a

18 (32%)a

660

RO

98 (65%)b

39 (68%)b

661

Sum

150 (49%)

LO

76 (48%)

663

RO

80 (52%)

664

Sum

156 (51%)

666 667 668 669

70 (34%)a

119 (50%)

137 (66%)b

118 (50%)

57 (29%)x

207 (41%)x

237 (49%)

69 (50%)

145 (50%)

116 (47%)

68 (50%)

148 (50%)

132 (53%)

137 (71%)y

293 (59%)y) 248 (51%)

TE D

665

PF/Contralateral

Ov. wave

ab Percentages in heifers with a different letter between sides and within the PF−CL pattern and each number of waves per IOI are different (P < 0.05).

EP

662

xy Percentages in heifers with a different letter between patterns within three waves per IOI are different (P < 0.05).

AC C

659

Sum

M AN U

Pattern/Relationship Side

Mares

SC

654 655 656 657 658

RI PT

651

670

No significant differences in mares between patterns, relationships, or sides.

671

Adapted from [42] with permission.

672 673

ACCEPTED MANUSCRIPT 32 674

Figure legends

675 Figure 1. Terminology in a monovulating species for diameter deviation (upper panel), switching

677

in follicle destiny between F1 and F2 during predeviation in wave 3 so that the smaller follicle

678

becomes dominant (middle panel) and between DF-to-CL relationships and among intraovarian

679

patterns (lower panel). The devoid pattern indicates an ovary with neither DF or PF nor CL. The

680

diameters for the upper two panels are for heifers. Although the diameters in mares and women

681

are larger, the relative diameters are similar among the three species.

SC

RI PT

676

M AN U

682

Figure 2. Frequency pathway for ovulatory wave 2 for IOI with a single ovulation at the

684

beginning and end of IOI; the remaining heifers had three-wave IOI (not shown). The number of

685

6-mm growing follicles in an ovary during the common growth phase (predeviation) was

686

determined in 105 of the 306 waves. The greater frequency of the PF in RO is attributable to

687

more 6-mm predeviation follicles in RO. Postdeviation, the frequency of the PF−CL pattern in

688

RO is greater than for LO but the frequency of the PF pattern is not different between ovaries;

689

that is, a greater frequency of RO ovulation occurred only when the CL was in the same ovary as

690

the PF. An asterisk indicates a difference (P < 0.05) between the indicated patterns. Designed

691

from published data [38,42]. CL, corpus luteum. IOI, Interovulatory interval. LO and RO, left

692

and right ovaries. NS, nonsignificant.

EP

AC C

693

TE D

683

694

Figure 3. Percentage of heifers that converted from an indicated PF-to-CL relationship of the

695

preovulatory period (ovulatory wave of previous IOI and preovulatory portion of wave 1) to the

ACCEPTED MANUSCRIPT 33 696

indicated DF-to-CL relationship of the postovulatory period (postovulatory portion of wave 1).

697

Alternating relationships occurred in 88% of conversions. Adapted from [49] with permission.

698 Figure 4. Left panel: Mean ± SEM for vascular perfusion index (1 minus resistance index) during

700

conversion of intraovarian patterns between the preovulatory and postovulatory periods. ab =

701

Indexes within conversion patterns with a different letter are different (P < 0.05). The number of

702

growing follicles is shown for each period. xyz = Number of follicles within each of the

703

preovulatory and postovulatory periods with no common letters are different (P < 0.05). Right

704

panel: An interpretation on the nature of the influence of an intraovarian pattern during the

705

preovulatory period on the postovulatory pattern of wave 1 through presumed continuity of

706

vascular perfusion and number of follicles per intraovarian pattern. Conversion of intraovarian

707

patterns from contralateral to ipsilateral relationships and from ipsilateral to contralateral are

708

depicted and interpreted above and below the broken line, respectively. The association of the

709

vascular index for each intraovarian pattern is shown for each conversion. Adapted from [49]

710

with permission.

SC

M AN U

TE D

EP

711

RI PT

699

Figure 5. Upper panel: Mean ± SEM for concentration of progesterone (P4) for four

713

permutations from two DF to CL relationships and two waves/IOI. The day of emergence of the

714

future DF at 6.0 mm for two-wave and three-wave IOI was 11 and 16 days after ovulation,

715

respectively. abc = within a day means with no common letter are different (P < 0.05). Adapted

716

from [47] with permission. Lower panel: Mean ± SEM for P4 and diameter of the future and

717

established DF normalized to the day of emergence of the follicle at 6.0 mm for the contralateral

AC C

712

ACCEPTED MANUSCRIPT 34 718

DF-to-CL relationship in wave 3. The diameter of DF on the day of the beginning of a mean

719

decrease in P4 is shown by the broken lines. Adapted from [58] with permission.

720 Figure 6. Mean ± SEM for color-Doppler signals of blood flow in the DF wall (upper panel) and

722

blood-flow signals in the CL tissue (lower panel) during waves 1 and 2 in two-wave IOI (N =

723

24). Ovarian patterns are DF−CL (DF and CL in the same ovary) and DF or CL (DF and CL in

724

opposite ovaries). The DF of waves 1 and 2 are designated DF1 and DF2, respectively. The

725

percentage of blood-flow signals were significantly different for DF and for CL within each

726

wave. The mean day of expected deviation is shown for each wave. DF1, dominant follicle of

727

wave 1. DF2, dominant follicle of wave 2. Adapted from [66] with permission.

M AN U

SC

RI PT

721

728

AC C

EP

TE D

729

ACCEPTED MANUSCRIPT

Terminology Established DF (F1)

Deviation

12

Common growth phase

10

Established largest subordinate (F2)

6

2

–3

14 12

Other subordinates

Future largest subordinate (F2) Deviation

SC

4

–2 –1 0 1 2 3 Days from diameter deviation

Switching

Spontaneous

10 8 6

4

M AN U

Follicle diameter (mm) in heifers

8 Future DF (F1)

RI PT

14

Induced

2 –1 0 1 Days from PGF2α

TE D

20 18 19 17 Days after ovulation

Intraovarian patterns

Preovulatory period

Ipsilateral relationship

Ipsilateral relationship

EP

Luteal period

Devoid

AC C

Contralateral relationship

5

Devoid Contralateral relationship

Figure 1.

ACCEPTED MANUSCRIPT

RO

Number of 6-mm follicles (1.8 ± 0.1)

Number of 6-mm follicles (2.3 ± 0.1)

PF−CL 52 (41%) Postdeviation

*

* 76 PF (59%)

PF−CL 98 (55%) NS

Preovulation

M AN U

* PF in LO 128 (42%)

*

EP

TE D

Fig. 2

AC C

PF 80 (45%)

SC

Common growth phase

LO

RI PT

Two-wave IOI 306 (61%)

PF in RO 178 (58%)

ACCEPTED MANUSCRIPT

Ovarian pattern conversions in heifers Postovulatory

Contralateral

Ipsilateral

PF CL

DF–CL Devoid

Ipsilateral

Contralateral

PF–CL Devoid Contralateral

Contralateral

PF CL PF–CL Devoid

M AN U

Ipsilateral

CL DF

Ipsilateral DF–CL Devoid

AC C

EP

TE D

Figure 3.

17 (65%)

6 (23%)

SC

CL DF

n (%)

RI PT

Preovulatory

1 (4%)

2 (8%)

ACCEPTED MANUSCRIPT Heifers

C

Preovulatory period

Postovulatory period

Number of follicles

b

PF

Contralateral relationship

Ipsilateral relationship

a

Increasing BF of developing PF. More 2-mm follicles

cl Devoid

6.6 z

1.5

b

Decreasing BF of regressing cl. Fewer 2-mm follicles

yz 7.1 y 1.4 c

CL DF

c

Decreasing BF of regressing cl. Fewer 2-mm follicles

Increasing BF after low levels. More 2-mm follicles

Ovulation

–2 –1

0

1

2

3

EP

–4 –3

Continued decrease in BF. Fewer 6 mm follicles opposes location of DF Contralateral relationship

Continued low BF. Fewer 6-mm follicles opposes location of DF

Devoid

c

TE D

Devoid

11.0 x

3.4x

M AN U

PF–cl

Continued increase in BF. More 6-mm follicles favors location of DF

Devoid

y

Ipsilateral relationship

a

4

–4

Days from ovulation

AC C

Vascular perfusion index

Continuation of angioarchitecture affects wave 1 intraovarian patterns

SC

b

DF–CL

2 mm 8.1y

6 mm 3.1 x

Postovulatory period

Angioarchitecture meets blood flow (BF) requirements of intraovarian patterns

RI PT

Preovulatory period

on

Vascular perfusion of ovary

of vascular pe uity rfu n i t si n o

Continued increase in BF. More 6-mm follicles favors location of DF

Pattern conversion

–3

–2

–1

0

Days from ovulation Figure 4.

1

2

3

P4

Heifers ACCEPTED MANUSCRIPT a

12

a

10

ab

8

b

a b

6

a

a

a

b

a a

b

4

b

2

c

c

0

b c

14 15 16 17 18 19 20 21 22 23 24 25 Days after ovulation 14

18

P4

12

16

10

14

DF

8

4 2 0 –3

–2

M AN U

12

6

–1

0

1

2

3

10 8 6 4 4

TE D

Days from follicle emergence at 6 mm in wave 3

AC C

EP

Figure 5.

Diameter (mm)

SC

Concentration (ng/mL)

Relationship Waves/IOI 2 waves Ipsilateral Contralateral 2 waves 3 waves Ipsilateral Contralateral 3 waves

a

RI PT

14

ACCEPTED MANUSCRIPT

Heifers Wave 1

DF2–CL

DF1–CL

30 20

DF1

DF2

10

80

M AN U

0 CL blood-flow DF1–CL signals

DF2–CL

CL

CL

60 40

TE D

% of CL tissue

RI PT

DF blood-flow signals

SC

% of follicle wall

40

Wave 2

20

Deviation 1

Deviation 2

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

AC C

EP

Days from ovulation Figure 6

ACCEPTED MANUSCRIPT

Highlights 1. Right ovary ovulation is more frequent in heifers and women but not in mares. 2. Right ovary ovulation is associated with greater oocyte quality.

AC C

EP

TE D

M AN U

SC

RI PT

3. A predilection for more follicles per wave favors right ovary ovulation.