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Infertility associated with the duration of luteal phase in postpartum cows

F. Perea G.1, E. Keith Inskeep2

Division of Animal and Nutritional Sciences, West Virginia University. Morgantown U.S.A. Recibido Diciembre 12, 2007. Aceptado Mayo 25, 2008.

ABSTRACT. After first postpartum most cows have a short luteal phase due to a premature secretion of PGF2a from the uterus. rate in estrous cycles with short luteal phases is essentially nil.

The lack of exposure of the uterus to P4 and prior to first postpartum ovulation decreases the concentration of P4 receptors and up regulates oxytocin receptors. The inadequate number of P4 receptors and presence of endometrial oxytocin receptors earlier in cows with short than normal luteal phases allows premature release of PGF2a and the resultant regression of the CL. During , uterine and luteal PGF2a cause death of the mainly during the transition from morula to when the embryos are more susceptible to embryotoxic effect.

Key words: postpartum, first ovulation, short luteal phase, infertility, .

Infertilidad asociada con la duración de la fase luteal en vacas postparto

RESUMEN. Luego de la primera ovulación postparto, la mayoría de las vacas presentan un ciclo estrual corto debido a la secreción anticipada de PGF2a desde el útero. La tasa de preñez en ciclos estruales con una fase luteal corta es prácticamente cero. La falta de exposición del útero a la P4 y estrógenos antes de la primera ovulación postparto, disminuye la concentración de receptores de P4 y estimula la expresión de receptores de oxitocina. El número inadecuado de receptores uterinos de P4 y la presencia de receptores endometriales de oxitocina mas temprano en vacas con ciclos estruales cortos que con ciclos estruales normales, permite la secreción prematura de PGF2a y la resultante regresión del cuerpo lúteo. Durante la luteólisis, la PGF2a de origen uterino y luteal causan la muerte embrionaria principalmente durante la transición de morula a blastocito, cuando los embriones son mas susceptibles al efecto embriotóxico.

Palabras clave: postparto, primera ovulación, fase luteal corta, infertilidad, ganado vacuno.

Introduction

The principal goal of cattle operations is to achieve The postpartum interval is a transition period calving and once every year, which allows during which the reproductive axis recovers after maximum expression of biological productivity, gestation to progressively reach the anatomical and leading to greatest milk and beef sales (Perea et al., functional status needed to initiate a new pregnancy. 2002). In order to accomplish this goal, conception The presence of dominant follicles in the ovaries, as should occur before day-90 postpartum. However, well as an adequate pattern of LH secretion, leads to several environmental, genetic, and physiologic the first postpartum ovulation a few weeks after factors can contribute to low and embryonic parturition (Murphy et al., 1990; Rajamahendran and losses once cows reinitiate reproductive cyclicity Taylor, 1990; Perea et al., 1998). Fertility at this first (Perea et al., 2005). estrual cycle is lower than in subsequent cycles,

1Autor para la correspondencia, e-mail: [email protected] 1Departamento de Ciencias Agrarias. Universidad de Los Andes. Trujillo. Venezuela 2Division of Animal and Nutritional Sciences, West Virginia University. Morgantown. USA.

ISSN 1022-1301. 2008. Asociación Latinoamericana de Producción Animal. Vol 16, número 3: 175- 185

175 176 Perea et al. mainly attributable to embryonic death during the et al., 1990; Stagg et al., 1995; Mackey et al., 2000). first two weeks after first (Wells et al., However, in cows induced to ovulate by early

1985; Inskeep, 2002). Premature secretion of PGF2α weaning or treatment with GnRH or hCG, the and early regression of the (CL) are occurrence ranged between 60 and 80% (Odde et al., responsible for the reduced conception rate (Cooper 1980; Kesler et al., 1980; Ramírez-Godinez et al., 1981; et al., 1991; Zollers et al., 1993; Inskeep and Dailey, Copelin et al., 1988; Johnson et al., 1992). Fertility 2004). Thus, maternal recognition of pregnancy is associated with first estrous cycles was lower than prevented, and a few days later the onset of a in subsequent cycles, which had normal lifespan of subsequent , which in turn has a nor- the CL (Odde et al., 1980; Ramirez-Godinez et al., 1982; mal conception rate (Odde et al., 1980; Ramirez- Breuel et al., 1993). Godinez et al., 1981). In fact, as will be documented in Physiologic bases of short luteal phase this review, the premature secretion of PGF2α in the In initial studies, short luteal phase was not first cycle is embryotoxic and the dies even if associated with either decreased luteotropic support exogenous is provided. by LH (Garcia-Winder et al., 1986; Copelin et al., 1988)

Short estrous cycles with sub-functional corpora or greater luteal sensitivity to PGF2α (Copelin et al., lutea (CL) are frequent before the first ovulatory estrus 1988; Figure 1). Non-suckled hysterectomized cows in peripubertal heifers (Berardinelli et al., 1979), in weaned at 23 to 30 days postpartum did not return to postpartum dairy (Menge et al., 1962; Morrow et al., estrus following first estrus, while intact cows had 1966) and beef (Corah et al., 1974) cows and as a estrual cycles averaged 8.8 days (Copelin et al., 1987; consequence of early weaning of beef calves (Bellows Figure 2). Although concentrations of P4 were similar et al., 1974; Odde et al., 1980). Treatment with from estrus to day 5, secretion of P4 decreased after progesterone (P4) prior to the first ovulation induces day 5 of the first cycle, but not after second estrus in a CL with normal lifespan (Ramírez-Godinez et al., intact cows or following the first or a second estrus

1981; Zollers et al., 1993; Fike et al., 1997) in a large (induced by PGF2α) in hysterectomized cows (Copelin proportion of cows. An experimental model for et al., 1987; Figures 1 and 2). Patterns of P4 before and comparisons of normal or short estrous cycles at the after day 5 postestrus in postpartum cows expected same stage postpartum was developed based on these to have CL of normal or short lifespan had similar facts. For short cycles, either early weaning or profiles (Zollers et al., 1989, 1991, 1993). Active treatment with GnRH, hCG or will suffice; immunization of anestrous beef cows against PGF2α whereas for normal estrous cycles, these same extended the lifespan and secretory capacity of CL treatments can be preceded by treatment with a (Copelin et al., 1989). The physiologic phenomenon . The model has been used extensively to has been described as a subnormal luteal phase study the mechanisms involved in short cycles occurring due to a premature release of PGF2α from following the first postpartum ovulation (Shefffel et the uterus and concomitant early CL regression al., 1982; Buford et al., 1996, Hernandez-Fonseca et (Copelin et al., 1987; Cooper et al., 1991). Presumably, al., 2000), as well as to find therapeutic alternatives lack of P4 caused death of the embryo and the onset of to improve reproductive efficiency during postpartum a new estrual cycle. anestrus (Butcher et al., 1992; Breuel et al., 1993; Schrick During normal estrous cycles, luteal phase P4 et al., 1993; Buford et al., 1996; Fike et al., 1997). allows a rise in estrogen to promote synthesis of P4 Characteristics of postpartum cattle receptors (Zollers et al., 1993) and to inhibit synthesis Resumption of ovarian cyclicity in Bos taurus dairy of uterine receptors for oxytocin through the mid- and beef cows takes place by around 30 or 60 days luteal phase (McCracken et al., 1984; Kieborz-Loos et following parturition, respectively (Roche et al., 1992), al., 2003). However, the lack of exposure of the uterus although this period is longer in tropical crossbred to P4 followed by estrogen prior to first postpartum cows (Bos taurus x Bos indicus) (Perea et al., 2002, 2005; ovulation decreases the concentration of P4 receptors Gonzalez et al., 2003). The occurrence of a short and up regulates oxytocin receptors, which allows interovulatory interval (7 to 12 days) is frequent after premature secretion of PGF2α (Cooper et al., 1991). first postpartum ovulation (Macmillan et al., 1971; Although embryonic death was presumably due to a

Odde et al., 1980; Ramirez-Godinez et al., 1982; Copelin lack of P4 support, exogenous P4 did not prevent et al., 1989; Zollers et al., 1989; Cooper et al., 1991; embryonic death, and evidence began to accumulate

Zollers et al., 1993). The incidence of short estrual that PGF2α might act as an embryotoxin (Butcher et cycles reported in postpartum cows ranged from 7 to al., 1992; Breuel et al., 1993). During luteolysis both

100% (Macmillan et al., 1971; Odde et al., 1980; Corah uterine and luteal PGF2α cause death of the embryos et al., 1974; Wells et al., 1985; Murphy et al., 1990; Savio mainly during the transition from morula to

ISSN 1022-1301. 2007. Asociación Latinoamericana de Producción Animal. Vol 16, número 3: 175-185 Infertility associated with the duration in postpartum cows 177

A B

PGF2α injection

Days Time (hours) Figure 1. Pattern of secretion of plasma LH (days 1 to 6) and prog esterone (days 0 to 16) after GnRH injection (day 0) in control (C; anticipated to have short luteal phase) and norgestomet pretreated hysterectomized (NH; anticipated to have normal luteal phase) cows (panel A). Mean (± SE) concentrations of

progesterone following injection of 10 mg of PGF 2α on day 7 in C and NH cows (panel B). Cows in NH group received a norgestomet implant for 9 days beginning 17 to 21 days post-calving. All cows were injected with 100 µg GnRH 28 to 32 days post-calving to induce ovulation, and in NH group, hysterectomy was p erformed 3 days later (reproduced from Copelin et al., 1988 with permission). blastocyst when the embryos are more susceptible to in postpartum beef cows undergoing premature luteal embryotoxins (Buford et al., 1996; Seals et al., 1998; regression than in those with a normal luteal phase Hockett et al., 2004). Furthermore, the process of (Cooper et al., 1991). Peter et al. (1989) found increased stimulates uterine secretion of PGF2a concentrations of oxytocin in association with and success rates have been improved by treatment increased concentrations of PGFM in dairy cows with with inhibitors of prostaglandin synthesis at or near short luteal phases, but Cooper et al. (1991) did not the time of transfer (Scenna et al., 2005). find consistent increases in oxytocin in association

Mean concentrations of PGF2α in vena caval plas- with increases in PGF2α in plasma from the inferior ma on days 4 to 9 after injection of hCG were greater vena cava of beef cows. Daily administration of

5 10 15 20 25 5 10 15 20 25 Day of estrous cycle

Figure 2. Pattern of secretion of plasma progesterone (mean± SE) in control and hysterectomized beef cows during the first and second estrous cycle. Calves were weaned at 23 to 33 days postpartum and cows were allotted to a control (sham surgery, n = 8) or a hysterectomy (n = 7) group (HG), with surgery

performed at weaning. Cows in HG were injected with 25 mg of PGF 2α approximately 20 days after first estrus (day 0). Blood samples were collected daily from surgery until completion of two estrous cycles (control) or until 24 days of the second estrous cycle (HG group) (reproduced from Copelin et al., 1987 with permission).

ISSN 1022-1301. 2007. Asociación Latinoamericana de Producción Animal. Vol 16, número 3: 175-185 178 Perea et al. oxytocin from day 2 postestrus in beef cows markedly only occurs at a specific time of the estrous cycle reduced length of the estrous cycle, but it did not (Lafrance and Goff, 1988; Silvia et al., 1991; Kieborz- appear to influence the rate at which P4 concentration Loos et al., 2003). It was believed that P4 suppressed increased during the first days after estrus secretion of PGF2α when more P4 receptors were (Donaldson et al., 1970). In postpartum cows, oxytocin present, presumably by inhibition of synthesis of induced a release of PGF2α on day 5 of a short but not oxytocin receptors early in the estrous cycle when a normal estrous cycle, and the oxytocin-induced the uterus was more responsive to P4 (McCracken et release of PGF2α on day 5 of the short estrous cycle al., 1984; Hazzard et al., 1998; Kieborz-Loss et al., was similar to that near to the time of luteolysis (day 2003). However, as the estrous cycle progressed,

16; Zollers et al., 1989). Moreover, in vitro secretion of concentrations of P4 receptors decreased, which in PGF from endometrial explants on day 5 was greater turn allowed the synthesis of estrogen and oxytocin for cows anticipated to have a short than a normal receptors (McCracken et al., 1984). As a result, the luteal phase (Zollers et al., 1991). Concomitantly, uterus became more responsive to oxytocin and a endometrial concentration of oxytocin receptors was positive feedback mechanism was apparently greater and mean number of P4 receptors per cell was established between oxytocin and endometrial PGF2α. lower on day 5 after estrus in postpartum beef cows In the normal estrous cycle of ruminants, a period expected to have short luteal phase (Figure 3) than in of progestational influence appears to be important cows receiving P4 pre-treatment and expected to have in the timing of luteal regression. Treatment with a normal luteal phase (Zollers et al., 1993). Although exogenous P4 on day 0 or 1 after estrus advanced the

P4 pre-treatment is necessary for normal luteal occurrence of the first peak of PGF2α and shortened lifespan and timing of uterine secretion of PGF2α the length of the estrous cycle in sheep (days 8 and 11 following first ovulation in cattle, early evidence for P4-treated ewes and days 12.3 and 17 for control indicated that oxytocin may be involved in premature ewes, respectively; Ottobre et al., 1980). In addition, secretion of PGF2α in cows with short estrual cycles. the blockade of P4 receptors by mifepristone (RU 486) Luteolysis during the estrous cycle in ruminants during the early to mid-luteal phase inhibited was believed to occur as consequence of a reciprocal luteolysis and preserved a functional corpus luteum positive feedback mechanism between luteal oxytocin beyond day 20, presumably due to insufficient PGF2α and uterine PGF2α (McCracken et al., 1984; Lafrance secretion from the (Morgan et al., 1993). and Goff, 1988; Lamsa et al., 1989). This mechanism Abolition of P4 source on days 12 or 14 by removal of was proposed to be responsible for the episodic either ovaries or CL in sheep, resulted in a temporal secretion of PGF2α necessary to complete luteal increase of PGF2α followed by a gradual decline regression (Flint et al., 1990); furthermore, this process (Ottobre et al., 1984; Vincent et al., 1986), suggesting

Short cycle Normal cycle Short cycle Normal cycle

Figure 3. Number of progesterone receptors per cell (left panel) and oxytocin receptor content (right panel) in bovine endometrial tissue († cytosolic; „ nuclear) on day 5 of a short or normal estrous cycle. Calves from cows in the short cycle group were weaned at 30-32 days postpartum, while cows in the short cycle group received norgestomet implant for 9 days at 21-23 days and their calves were weaned at implant insertion. On day 5 following first postpartum ovulation, two group of cows were hysterectomized and endometrial tissue was collected for measurement of oxytocin and progesterone receptors (reproduced from Zollers et al., 1993 with permission).

ISSN 1022-1301. 2007. Asociación Latinoamericana de Producción Animal. Vol 16, número 3: 175-185 Infertility associated with the duration in postpartum cows 179 that continued secretion of P4 is necessary for secretion follicles from cows that would have a short luteal of PGF2α to continue beyond day 14 of the estrous phase (Sheffel et al., 1982; Garcia-Winder et al., 1986) cycle. Apparently, P4 regulates secretion of PGF2α by could reduce uterine P4 receptor synthesis (Zollers et timing the initial peaks of secretion early in the estrous al., 1993) and consequently the first rise in P4 is cycle, and thereafter, by modulating secretion of followed by early secretion of PGF2α (Cooper et al.,

PGF2a until luteal regression is completed. However, 1991), which shortened the luteal phase. in postpartum cows and anestrous ewes the absence A confirmatory study of previously documented of a previous exposure of the uterus to P4 followed by findings was carried out by Kieborz-Loos et al. (2003). estrogen prior to first ovulation alters the Postpartum anestrous cows exposed or not to physiological conditions of the uterus and as a different combinations and/or sequences of consequence, the timing of luteolysis. exogenous estradiol-17b and P4 were ovariectomized Endocrine events conducive to short or normal on day 23 or 32 after calving. Oxytocin was injected luteal phase at the end of each treatment to test the ability of the

Preovulatory follicles from anestrous beef cows postpartum uterus to secrete PGF2α. Oxytocin- pre-treated with the synthetic progestogen, induced secretion of PGF2α was greater on day 16 norgestomet, were larger and contained more than on day 6 of a simulated normal luteal phase, estradiol-17b than those of control cows with short implying that steroid treatment (P4 followed by estrous cycles (Sheffel et al., 1982; Garcia-Winder et estradiol) stimulated the uterine responsiveness to al., 1986). Furthermore, greater concentrations of oxytocin similar to that observed at end of a normal receptors for LH, in both granulosa and theca, and estrous cycle (Lafrance and Goff, 1988). However, greater concentrations of estradiol were detected in neither P4 alone nor estradiol-17b followed by P4 the largest preovulatory follicles collected from treatment were capable of reducing PGF2α secretion postpartum cows treated with norgestomet than from on day 6 of a simulated estrual cycle in control cows (Inskeep et al., 1988; Table 1). In addition, ovariectomized cows. Only when estradiol-17b/P4 postpartum anestrous cows treated with a treatment was preceded by a period of P4 priming, subcutaneous ear implant containing estradiol-17b exogenous oxytocin was unable to provoke an for 40 days after calving had approximately 40% increased secretion of PGF2α on day 6 of the fewer short estrous cycles during the time of estradiol simulated cycle (Kieborz-Loos et al., 2003). In exposure than non-treated cows (Day et al., 1990). postpartum anestrous cows, comparatively more Increased concentrations of estradiol have been cows ovulated and formed CL with typical lifespan associated with induction of endometrial P4 receptors after treatment with a P4 releasing intravaginal device (Zelinski et al., 1980; Ing et al., 1997). Therefore, lower alone or in combination with (EB) concentrations of estradiol secreted by preovulatory than when cows were treated with only EB or were

Table 1. Concentrations of LH and FSH receptors, weights of follicular components and amounts of estradiol in follicular fluid from largest follicles of postpartum cows treated or not with a progestogen and expected to have a normal or short lifespan of the corpora lutea (Modified from Inskeep et al., 1988).

Variables Treatment Significance

Control Norgestomet

Number of cows 11 11 LH receptors (fmol/mg): Granulosa 1.16 ± 0.25 1.78 ± 0.16 P < 0.01 Theca 0.31 ± 0.04 0.73 ± 0.11 P < 0.01 Weight Entire follicle (g) 1.26 ± 0.10 2.66 ± 0.29 P < 0.01 Theca (mg) 136.1 ± 8.3 171.8 ± 17.8 P < 0.10 Granulosa (mg) 65.4 ± 4.8 101.4 ± 19.1 P < 0.10 Fluid (g) 1.06 ± 0.09 2.38 ± 0.26 P < 0.01 Estradiol in fluid: Content (ng/follicle) 4.28 ± 1.71 23.43 ± 6.49 P < 0.05 Concentration (ng/g fluid) 3.87 ± 1.54 9.36 ± 2.19 P < 0.05

ISSN 1022-1301. 2007. Asociación Latinoamericana de Producción Animal. Vol 16, número 3: 175-185 180 Perea et al. untreated controls (C) (Fike et al., 1997). Interestingly, after estrus, maintained pregnancy in cows with the addition of EB enhanced the proportion of cows short-lived CL (Breuel et al., 1993). Thus, premature with normal length of the estrual cycle (P4+EB: 76%; regression of the CL was not the only factor responsible

P4: 57%; EB: 24%; C: 19%). for the low fertility associated with the short luteal What is the source of the steroids that assure a phase. normal lifespan of the CL in those cows during Two good-quality embryos were transferred on spontaneous ovulatory cycles after calving? In day 7 into cows induced to have short or normal luteal prepubertal heifers, Berardinelli et al. (1979) showed phases and supplemented with daily doses of P4 from that small luteal tissue embedded in the ovarian day 4 to 35. Pregnancy rates were 28% and 56% for stroma and surrounded by connective tissue were short and normal luteal phases, respectively (Butcher responsible for increases in P4 before first normal et al., 1991). In a later study, uterine horns ipsilateral ovulatory cycles. In addition, a gradual rise in P4 prior to the CL from cows induced to have short or normal to the first postpartum estrus has been reported in luteal phases were flushed nonsurgically and cattle (Donaldson et al., 1970; Corah et al., 1974; Perry embryos were transferred into recipient cows with et al., 1991; Dimmick et al., 1991; Breuel et al., 1993). normal estrous cycles (Schrick et al., 1993). Quality

Increased P4 3 days before first postpartum estrus was and stage of development of embryos on day 6 did detected in primiparous cows that conceived, while not differ among groups. Pregnancy rate did not differ no elevation prior to estrus was detected in those cows after embryos were transferred into cycling recipients that failed to conceive and had a short estrous cycle (50 vs 72% for embryos from short and normal cycles, (Corah et al., 1974). Also, Ramirez-Godinez et al. (1981) respectively). However, on the basis of donor animals, reported that 7 cows with estrous cycle of at least 17 only 23% of recovered embryos from short cycles were days had a significant rise in serum progesterone ultimately successful compared to 46% prior to the first detected estrus. from normal cycles. Apparently, both detrimental The occurrence of ovulations in absence of clinical factors that affected the or embryos before day signs of estrus frequently observed in postpartum 7 and an improper uterine environment after day 7 cows spontaneously reinitiating ovarian activity could contribute to early embryonic death (Butcher et might account for the particular sequence of endocrine al., 1991; Schrick et al., 1993). events required for a normal luteal phase (Stevenson Embryotoxic effect of prostaglandin F2α and Britt, 1979; Fike et al., 1997; Henao et al., 2000). In Inskeep (1995) stated that subluteolytic this regard, Castenson et al. (1976) reported that the concentrations of PGF2α could play a role in increase in P4 prior to first postpartum estrus was embryonic death during early development via produced by a short lived CL, presumably from release of an embryotoxin from the CL. In ovulation because of the presence of a stigma. A more characterizing such embryotoxic factors, Schrick et recently study using ultrasonography supported al. (1993) found concentrations of PGF2α in uterine those findings (Perry et al., 1991). flushings to be greater in cows with short than nor- Fertility and embryo viability in cows with short mal luteal phases on day 6; the most relevant finding luteal phase was that the more PGF2α in the uterine fluid the lower As reviewed above, the first spontaneous or the quality of the embryos (r = -0.42; P<0.07). induced ovulation after calving is associated with a Therefore, a detrimental uterine environment CL of short lifespan (for review see: Inskeep, 1995; appeared to be a major cause of low fertility in cows 2002; Inskeep and Dailey, 2004). Even when first with short luteal phases after first ovulation (Schrick ovulation is preceded by estrus, fertility in beef cows et al., 1993). is lower than in first normal length or subsequent A series of experiments was designed to study the estrous cycle (Ramirez-Godinez et al., 1981; Breuel et role of the PGF2α in reducing fertility in cows with al., 1993). Fertilized oocytes in different stages of short luteal phases. Cycling cows were injected every development were recovered from oviduct and uterus 8 hours with saline (control), PGF2α or flunixin (on days 3 and 6 after first estrus, respectively) from meglumine (an inhibitor of prostaglandin cows with a short-lived CL (Ramirez-Godinez et al., endoperoxide synthetase), on days 4 through 7 or 5

1982; Breuel et al., 1993; Schrick et al., 1993). The failure through 8, and supplemented with exogenous P4 to sustain pregnancy was presumed to be due to early twice daily from day 3 until pregnancy diagnosis was luteal regression, as indicated by serum performed. In one group of PGF2α-treated cows, the concentrations of P4 (Ramirez-Godinez et al., 1982). CL was removed on day 7. As expected, pregnancy

Surprisingly, neither daily provision of melengestrol rate was lower in cows treated with PGF2α compared acetate nor twice daily injection of P4 from day 4 to 35 with those that received saline or flunixin meglumine

ISSN 1022-1301. 2007. Asociación Latinoamericana de Producción Animal. Vol 16, número 3: 175-185 Infertility associated with the duration in postpartum cows 181 (Figure 4), but surprisingly, pregnancy was restored In subsequent studies pregnancy rate was lowered to normal when treatment with PGF2α was by daily dosage with PGF2α, on day 5 through 8 (23%) accompanied by lutectomy (Buford et al., 1996). but not on days 10 to 13 (50%) or 15 to 18 (60%) after

Cows induced to have short estrous cycles by mating of P4-supplemented cows (Seals et al., 1998). weaning at 25 to 31 days postpartum were treated Treatment of P4-supplemented cows with PGF2α on with saline (S), flunixin meglumine (F), flunixin day 5 through 8 reduced quality and retarded meglumine plus lutectomy or lutectomy only (L), on development of embryos (Hockett et al., 2004). Also, days 4 through 9, and supplemented with exogenous PGF2α in vitro reduced the ability of 26 to 32-cell progesterone twice daily from day 3 until pregnancy bovine embryos to develop to (Scenna et diagnosis. Pregnancy rate did not differ among S, F al., 2004). Therefore, PGF2α may interfere with the and L groups (< 21%). However, pregnancy rate was process of compaction of the embryo at the morula higher (50%; Figure 4) when lutectomized cows were stage (Hockett et al., 2004), probably by alterations in treated with flunixin meglumine (Buford et al., 1996). gap junctions and cell adhesion molecules, induction That treatment would have reduced secretion of of apoptosis mechanisms or alterations of gene

PGF2α by the uterus and removed the CL as a source transcription during embryonic development (Scenna of PGF2α. Moreover, in ewes treated with PGF2α on et al., 2004). days 4 through 7 after mating and supplemented with In order to test whether the luteal source of the an intravaginal progestogen, lutectomy increased embryotoxin was delivered by a systemic or a local pregnancy rate (59%) compared with sham lutectomy pathway, beef heifers and cows received one good (33%; Costine et al., 2001). quality embryo into each uterine horn on day 6 or 7 of

In summary, lutectomy and the inhibition of the estrual cycle, and P4 replacement therapy from prostaglandin synthetase prevented the negative transfer through day 35 (Hernandez-Fonseca et al., effects of endogenous PGF2α on the early embryonic 2000). Each female was injected with three daily stage in postpartum cows (Buford et al., 1996), therapeutic doses of PGF2α or saline from day 5 whereas lutectomy alone was effective in nonlactating through 8. Survival of embryos placed into the uterine cycling cows (Buford et al., 1996), and ewes (Costine horn adjacent or opposite to the CL was not different et al., 2001) treated with exogenous PGF2α. Therefore, and no evidence was found to support the existence the lower embryo survival in postpartum cows of a local embryotoxic effect originated from the appeared to be due to the combined effect of uterine regressing CL. Therefore, embryotoxicity probably

PGF2α secreted on days 4 through 9 (Cooper et al., involved compounds that either act systemically or

1991) and the luteal secretion of PGF2α in response to were transported via the uterine lumen to the uterine the uterine signal (Buford et al., 1996). horn contralateral to regressing CL (Hernandez-

100 90 80 70 60 * 50 40 30 * Percent pregnant Percent 20 10 0 CON PGF FM PGF+L CON FM LUT FM+L Cyclic cows Postpartum cows Treatments

Figure 4. Pregnancy rates in cyclic (left) and postpartum (right) beef cows at 30 days of induced estrous. Exogenous progesterone was injected twice daily from day 3 or 4 until pregnancy diagnosis was

performed. Cows were mated and injected every 8 h with saline (CON), prostaglandin F 2α (PGF), flunixin meglumine (FM) and PGF and lutectomy (PGF+L) on days 4 through 7 or 5 through 8 postestrus (cyclic cows); or saline, FM, L, and FM+L on days 4 through 9 postestrus (postpartum cows). Treatment differed (P<0.05) within type of cow if an asterisk is present (adapted from Buford et al., 1996 with permission).

ISSN 1022-1301. 2007. Asociación Latinoamericana de Producción Animal. Vol 16, número 3: 175-185 182 Perea et al. Fonseca et al., 2000). In a similar experiment in sheep, it was accompanied by lutectomy (30%). However, the embryotoxic effect of the regressing CL also was pregnancy rate was restored to normal (80%) if demonstrated; again, there was evidence that the effect oxytocin-treated cows also received a prostaglandin occurred through a systemic pathway (Costine et al., synthesis inhibitor. Therefore, the oxytocin acted

2001). through stimulation of uterine secretion of PGF2α. Is oxytocin involved as an embryotoxic Given that a regressing CL was required to manifest component of the regressing corpus luteum? the negative effect of PGF2α on embryo survival At the time of Inskeep’s review in 1995, oxytocin (Buford et al., 1996; Seals et al., 1998), it could be was included in the list of factors that could play a concluded removal of luteal tissue reduced the lethal role in embryonic death in cows with short luteal effect by interruption of the modulatory effect of phases. As was previously pointed out, luteal oxytocin on uterine PGF2α secretion (Lemaster et al., oxytocin and uterine prostaglandin were believed to 1999) and by abolition of PGF2α secreted from CL participate in luteolysis through a reciprocal positive once luteolysis was initiated (Rexroad and Guthrie, feedback mechanism (McCracken et al., 1984). 1979). Therefore, a direct embryotoxic effect of oxytocin Concentrations of endometrial oxytocin receptors on embryo development is improbable. were greater at day 5 after estrus in cows with short Niswender et al. (2007) summarized evidence that lifespan of the CL than in cows receiving P4 pre- luteal PGF2α is involved in luteolysis in sheep. Once treatment and expected to have a normal luteal phase the uterine signal (PGF2α) initiates increased luteal ++ (Zollers et al., 1993). Greater concentrations of secretion of PGF2α, it triggers mobilization of Ca in oxytocin were evident 30 minutes after first injection large luteal cells and secretion of oxytocin by these ++ of PGF2α in P4-supplemented cows treated three ti- cells. Oxytocin in turn, triggers mobilization of Ca ++ mes daily with PGF2α on day 5 to 8 after estrus in small luteal cells. Apoptosis follows Ca compared with cows injected with PGF2α and mobilization in both cell types. Thus, secretions from lutectomized (Buford et al., 1996). Lemaster et al. (1999) the CL are involved in its demise, acting within the tested the possibility of a role for oxytocin. CL itself. Administration of oxytocin on day 5 through 8 As conclusion, Figure 5 indicates the sequence of decreased the embryonic survival in progestogen- endocrine events conducive to embryonic death or supplemented beef (pregnancy rate: 33.3%) even when survival in short and normal estrous cycles.

ISSN 1022-1301. 2007. Asociación Latinoamericana de Producción Animal. Vol 16, número 3: 175-185 Infertility associated with the duration in postpartum cows 183

Hypothalamus

Anterior Pituitary

Previously ovulated LH FSH Not previously or exogenous P4 ovulated

Ovarian follicular development ↑ LH receptors Low LH receptors ↑ P4 Low P4 ↑ E2 receptors Low E2 receptors

Ovulation

↑ P R Low P R 4 Uterus 4 ↓ OTR High OTR

↑ PGF2α days 14 to 17 ↑ PGF2α days 4 to 9

Corpus luteum Luteal PGF2 Luteal Normal luteal Uterine PGF2 Short luteal phase phase

, PGE ↓ P4 τ α INT- α of pregnancy Maternal recognition Maternal Embryo

Survival Death

Figure 5. Sequence of endocrine events conducive to embryonic death or survival in short and normal estrous cycles. After parturition, hypothalamic-pituitary axis stimulates progressively ovarian follicular development, estradiol production and expression of LH receptors in the follicle. Without a previous

cycle or exposure to P4 followed by estrogen (E2), uterine P4 receptors (P4R) are low and the increase in P4 after ovulation initiates immediate secretion of uterine prostaglandin (PG) F2α which causes luteolysis and, if the animal has been mated, is embryotoxic. Exposure of the uterus to P4 followed by E2 prior to first postpartum ovulation up regulates uterine P4R and contributes to establishment of P4 dominance of the uterus. As the estrual cycle progresses, P4 binding to its receptors delays uterine secretion of PGF2α. If the animal is not mated/pregnant luteolysis is initiated by uterine secretion of PGF2α that starts around day 14 to 17 and decreases P4 production. If pregnant, the embryo produces interferon-τ (INT-τ), the uterus increases secretion of PGE and the corpus luteum is maintained allowing the embryo to survive. This process is called maternal recognition of pregnancy.

ISSN 1022-1301. 2007. Asociación Latinoamericana de Producción Animal. Vol 16, número 3: 175-185 184 Perea et al. Literature cited

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