Effects of Dietary Energy on Control of Luteinizing Hormone Secretion

in Cattle and Sheeplr’

Keith K. Schillo

Department of Animal Science, University of Kentucky, Lexington 40546-02 15

ABSTRACT: Prolonged restriction of dietary energy delays onset of puberty, disrupts cyclicity in sexually mature animals, and lengthens the postpartum anestrous period in domestic ruminants. One important mechanism by which energy restriction impairs reproductive activity seems to be suppression of the increase in LH pulse frequency that is necessary for growth of ovarian follicles to the preovulatory stage. Under- nutrition apparently inhibits pulsatile secretion of LH by reducing LHRH secretion by the hypothala- mus. The ability of an animal to sustain a high- frequency mode of pulsatile LH release is related to its metabolic status. Mechanisms linking meta- bolic status to LHRH secretion have not been fully

characterized. Changes in body fat have been associated with changes in reproductive activity, but it is unlikely that body fat per se regulates LHRH secretion. It is possible that pulsatile LHRH release is regulated by specific metabolites and(or1 metabolic hormones that reflect nutritional status. Alternatively, availability of oxidizable metabolic fuels, such as glucose and nonesteflied fatty acids, may influence activity of neurons that control LHRH release. Our understanding of how the central nervous system transduces informa- tion about nutritional status into neuroendocrine signals that control reproduction in cattle and sheep is limited by a lack of information concern- ing the nature of neurons controlling LHRH release in these species.

Key Words: Energy Intake, Reproduction, LH, Ruminants

Introduction

Inadequate nutrition impairs reproductive func- tion in many mammalian species. Effects on domestic ruminants include delayed onset of pu- berty (Foster and Olster, 1985; Day et al., 19861, induction of anestrus in cyclic females (Imakawa et al., 1983, 1984, 1986a, 1987; Richards et al., 19891, and prolonged postpartum anestrus (Randel, 19901. Detrimental effects of undernutrition on reproduc- tion in female animals could be exerted at the level of the ovary, anterior pituitary gland, and(or1 hypothalamus. Dietary energy restriction has

‘Presented at a symposium titled “NutritiodEndocrine Interactions” at the 1991 Midwestern ASAWADSA Mtg., Des Moines, IA.

2This paper (no. 91-5-53] is published with approval of the director of the Kentucky Agric. Exp. Sta.

Received May 2, 1991. Accepted October 24, 1991.

J. Anim. Sci. 1992. 70:1271-1282

been shown to suppress episodic release of LH in cattle (Imakawa et al., 19871 and sheep (Thomas et al., 1990). A high-frequency mode of pulsatile LH secretion is important for the final phase of maturation of ovarian follicles (Hansel and Con- vey, 1983; Kinder et al., 1987; Randel, 1990) and thus for induction of estrus and ovulation. There- fore, an important mechanism by which nutrition influences reproductive activity may involve ef- fects on neuroendocrine control of LH release. The purpose of this review is to summarize the effects of dietary energy restriction on LH secretion during several reproductive states and discuss current theories concerning how information re- garding nutritional status is generated, detected, and transduced into signah that influence LH secretion in cattle and sheep. This discussion will focus on dietary energy rather than dietary pro- tein or other nutrients, because most studies concerning effects of nutrition on reproduction involve restriction of dietary energy.

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Published December 11, 2014

1272 SCHILLO

Neuroendocrine Control of Luteinizing Hormone Secretion

It is well established that LH is released from the anterior pituitary gland in a pulsatile manner (Butler et al., 1972; Rahe et al., 1980). The release of LH is controlled by LHRH, a decapeptide, released into the hypothalamic-hypophysial portal vascular system by neurosecretory cells located in the hypothalamus (McCann, 1974). Recent data finnly established that the pattern of LH in the periph- eral circulation reflects the pattern of LHRH release (Levine and Ramirez, 1980, 1982; Levine et al., 19821. It is presumed that a neural oscillator directs LHRH secretion, but the exact nature of this system is unknown. It is apparent, however, that a variety of neuronal inputs conveying infor- mation about an animal's internal and external environments modulate this system. For example, ovarian steroids (Goodman and Karsch, 19801, nutritional status (Foster and Olster, 19851, and photoperiod (Legan and Karsch, 19791 influence frequency of LH pulses in sheep.

Research conducted with monkeys lead to the concept that the pulsatile pattern of LH release is important in controlling ovarian function (Knobil, 19811. Increases in LH pulse frequency have been documented in cattle and sheep during the follicu- lar phases of their estrous cycles (Hansel and Convey, 19831, before puberty (Kinder et al., 19871, and preceding first ovulation postpartum (Malven,

INHIBITION OF RELEASE FROM

-

j_

Figure 1. Endocrine events leading to follicular growth, estrus, and ovulation in cattle and sheep. During the prepubertal period, postpartum period, and luteal phase of the estrous cycle, luteinizing hormone (LH) pulse frequency is low [I pulse/ 6 to 8 h) due to inhibitory effects of estradiol (E2), suckling, and proges- terone, respectively. Reduced sensitivity to estradiol, recovery from the suckling stimulus, and decrease in progesterone due to luteolysis allow LH pulse fre- quency to increase (1 to 2 pulsedh). The increase in LH stimulates follicle growth and E2 production, which induces estrus and the preovulatory surge of LH.

1984). In addition, induction of high-frequency LH pulses with intermittent injections of LH or LHRH induced ovulation in acyclic primates exhibiting a low frequency of endogenous LH pulses (Wildt et al., 1980; Pohl et al., 1983; Skarin et al., 1983). Together, these observations suggest that a high- frequency mode of pulsatile LH release is critical for stimulating follicle growth to the preovulatory stage, and thus for induction of estrus and ovulation (Figure 11.

Onset of Puberty

As indicated previously, the critical event lead- ing to onset of puberty in cattle and sheep is the prepubertal increase in LH pulse frequency that results from a decrease in responsiveness of the hypothalamic-pituitary axis to estrogen negative feedback (Kinder et al., 1987). This increase in pulsatile LH secretion stimulates development of ovarian follicles to the preovulatory stage. Results of several experiments support the hypothesis that undernutrition prevents onset of puberty in the lamb by blocking the prepubertal increase in LH pulse frequency. A series of experiments con- ducted by Foster and Olster (19851 demonstrated that ewe lambs fed to maintain their weaning weights were anovulatory at a time when lambs allowed ad libitum access to feed became puber- tal. Undernutrition also reduced pulsatile LH secretion in ovariectomized lambs both in the absence and presence of estradiol negative feed- back. In addition, undernutrition did not influence estradiol-induced surges of LH in ovariectomized lambs, but it reduced the amplitude of the surges in ovariectomized lambs that were chronically pretreated with physiological amounts of estradi- ol. McShane and Keisler (19901 demonstrated that hourly injections of LH in underfed lambs induced follicular growth, LH surges of normal amplitude, and ovulation. Based on these observations, it seems that disruption of pulsatile LH secretion is the primary mechanism whereby undernutrition delays onset of puberty in the lamb. Foster et al. (1989) demonstrated that nutritionally growth-re- stricted lambs exhibited depressed LH pulse fre- quencies, but that concentrations of growth hor- mone (GH1 and prolactin were not suppressed. This indicates that low nutrition does not impair release of all anterior pituitary hormones.

Several studies have focused on how energy restriction impairs pulsatile LH secretion. Plane of nutrition did not affect pituitary concentrations of LH in ovariectomized lambs, but lambs allowed ad libitum access to feed had higher levels of mRNA for both subunits of LH than lambs maintained on a restricted amount of feed (Landefeld et al., 1989).

NUTRITION AND LH SECRETION 1273

Underfed, agonadal lambs responded normally to physiological doses of LHRH (Foster et al., 19891, suggesting that anterior pituitary gland function was not compromised by undernutrition. The effects of undernutrition on LH secretion seem to be manifested at the level of the central nervous system. N-methyl-d,l-aspartate, a stimulator of LHRH release, induced LH release in ovariecto- mized lambs subjected to chronic food restriction (Ebling et al., 1990; I’Anson et al., 19901. In addition, hypothalamic LHRH content was the same for underfed lambs and lambs allowed ad libitum access to feed (Ebling et al., 1990). The latter observation suggests that the effects of feed restriction are exerted on central mechanisms controlling LHRH release rather than on LHRH synthesis.

The effect of undernutrition on timing of pu- berty onset in the heifer seems to be similar to that in the lamb. Heifers maintained on a low-energy diet failed to exhibit an increase in LH pulse frequency at a time when heifers fed a diet adequate for growth exhibited increased LH pulse frequencies and attained puberty (Day et al., 1986). More recently, Kurz et al. (1990) examined the effects of nutrition on LH patterns in ovary-intact, ovariectomized, and ovariectomized, estradiol- treated heifers. Restriction of dietary energy prevented the prepubertal increase in LH pulse frequency in intact heifers as well as in ovariecto- mized heifers both in the presence and absence of estradiol. Increased energy intake induced an increase in LH pulse frequency within 14 d regardless of endocrine status. Effects of dietary energy restriction on amplitudes of endogenous LH pulses and LHRH-induced release of LH in heifers are not consistent. Day et al. (1986) re- ported that dietary energy restriction reduced LH pulse amplitude and response to LHRH. In a subsequent study murz et al., 19901, dietary energy restriction increased amplitude of LH pulses and response to LHRH. These latter observations are consistent with the hypothesis that dietary energy restriction reduced frequency of LHRH pulses, resulting in enhanced pituitary stores of LH.

The previous discussion implies that inadequate dietary energy prevents onset of puberty by suppressing pulsatile release of LH, a mode of action that probably involves inhibition of LHRH secretion by the hypothalamus.

Estrous Cycle

Prolonged restriction of dietary energy induced anestrus in sexually mature cattle (Bond et al., 1958; Imakawa et al., 1983, 1984, 1986a, 1987; Richards et al., 1989). This effect was partially

attributed to a decrease in LH secretion. Heifers fed low levels of dietary energy failed to exhibit pulsatile patterns of LH after withdrawal from progestin/estrogen treatment (Imakawa et al., 19841. In another experiment (Imakawa et al., 1986131, frequency of LH pulses during the follicular phase of the estrous cycle was correlated posi- tively with change in body weight. Anestrus resulting from poor nutrition was associated with a decrease in frequency of LH pulses in beef heifers (Richards et al., 19891, an effect that was apparently due to enhanced responsiveness to estrogen negative feedback as well as a direct, steroid-independent effect on LHRH release (Im- akawa et al., 1986a, 1987).

Adult ewes maintained on low planes of nutri- tion exhibited reduced ovulation rates (Haresign, 19811, a response attributed to reduced ovarian follicular development (McNeilly et al., 1987) rather than to an alteration of the preovulatory surge of LH. Effects on follicular development could result from disruption of pulsatile LH re- lease. Ovariectomized ewes maintained on a low- energy diet that resulted in a 4 2 % weight loss exhibited fewer LH pulses and lower mean concen- trations of LH in serum and anterior pituitary gland but increased concentrations of LHRH in hypothalamic tissue compared with ewes fed a maintenance diet (Tatman et al., 1990). Inhibitory effects of feed restriction on frequency of LH pulses in ovariectomized ewes have also been demonstrated by Thomas et al. (1990). Collectively, these results suggest that dietary energy restric- tion impairs pulsatile LH secretion by decreasing hypothalamic release of LHRH. This hypothesis is supported further by the fact that pulsatile admin- istration of LHRH restored concentrations of LH in serum and the anterior pituitary gland and mRNA for the a and p subunits of LH in underfed, ovariectomized, estradiol-treated ewes during the breeding season (Kile et al., 1991). Thomas et al. (1990) failed to detect effects of undernutrition on pituitary concentrations of mRNA for LH subunits in ovariectomized ewes not treated with estrogen.

The effect of undernutrition on ability of the anterior pituitary gland to respond to LHRH has not been studied thoroughly in sexually mature animals. It is doubtful that the negative effects of inadequate nutrition on LH secretion involve changes in pituitary responsiveness to LHRH. Dietary energy restriction did not influence num- ber of pituitary receptors for LHRH (Tatman et al., 1990). Underfed, ovariectomized ewes released LH in response to LHRH injections (Kile et al., 19911, but their responses were not compared to those of well-fed animals. Furthermore, the effects of differ- ent doses of LHRH on LH release have not been evaluated with respect to nutritional status; hence,

1274 SCHILLO

firm conclusions cannot be made regarding more subtle effects of nutrition on sensitivity of the pituitary gland to LHRH.

Long-term feed restriction in adult, ovariecto- mized ewes reduced frequency of LH pulses and increased GH concentrations but did not influence prolactin concentrations [Thomas et al., 1990). This agrees with work done with ovariectomized lambs and supports the concept that low nutrition does not impair secretion of all anterior pituitary hormones.

In summary, nutritional anestrus and reduced ovulation rate in adult cattle and sheep involve disruption of pulsatile LH release, but direct effects on the ovary are also possible. The nega- tive effects of inadequate nutrition on LH release seem to be manifested at the level of the central nervous system and probably involve reduced LHRH release.

Postpartum Period

Malven (1984) reviewed the major physiological events leading to postpartum rebreeding and concluded that the following events are required for successful rebreeding of postpartum cows: recovery of the pituitary gland and uterus from the pregnant state, escape from suckling-induced inhibition of pulsatile LH secretion, ovarian follicu- lar development, estrus, ovulation, and adequate luteal function. The effects of undernutrition on postpartum rebreeding were reviewed recently by Short and Adams (1988) and Randel (1990). Restric- tion of dietary energy late in the prepartum period or early in the postpartum period reduced the number of animals returning to estrus within a well-defined breeding season. These effects are apparently attributed to a failure to develop preovulatory ovarian follicles.

Detrimental effects of undernutrition on ovarian activity could be due to effects on any of the components of the reproductive endocrine axis. Intermittent injections of LHRH for 2 wk begin- ning 21 d after calving increased the number of suckled cows ovulating during the treatment period. The response was reduced in cows that were subjected to energy restriction before calving relative to cows that received adequate nutrition (Short and Adams, 1988). The fact that LHRH induced LH pulses in all animals indicates that the ovary may not have responded to the LH signal in all the underfed cows. Peters et al. (1985) reported that very few lactating cows ovulated in response to pulsatile administration of LHRH when deli- vered at a time when animals were in a negative energy balance. Canfield and Butler (1991) re-

ported that dairy cows in a negative energy balance had similar LH patterns but ovulated later than cows in positive energy balance. Togeth- er, these results support the hypothesis that some effects of undernutrition may involve reduced ovarian responsiveness to LH.

The effect of nutritional status on pituitary responsiveness to LHRH in postpartum cows has been the focus of several studies. Dietary energy restriction has been reported to either increase (Whisnant et al., 19851, decrease (Lishman et al., 1979; Rutter and Randel, 19841, or not affect (Entwistle and Oga, 1977) LHRH-induced release of LH in postpartum cows. Differences in responses may be attributed to variations in level of dietary energy restriction, metabolic status of cows, or time of treatment during the postpartum interval. Moss et al. (1985) demonstrated that both nutri- tional status and days postpartum influenced pituitary stores of LH but not number of pituitary LHRH receptors.

The ability of estradiol to induce a preovulatory surge of LH also seems to be influenced by nutritional status of the postpartum cow. Echter- nkamp et al. (1982) found that estradiol-induced surges of LH in underfed cows occurred later and with lower amplitudes than those in well-fed cows.

Surprisingly few studies have examined the effects of dietary energy restriction on pulsatile release of LH during the postpartum period. Cows fed a low-energy diet before calving exhibited a lower frequency of LH pulses than cows that received a higher plane of nutrition at 14, 42, and 70 d after parturition (Perry, 1990). Whisnant et al. (1985) reported that underfed, postpartum cows had lower LH pulse frequencies than well-fed cows, but this effect was present during suckling or within 1 d after calf removal and disappeared 2 d after calf removal. This suggests that the effects of undernutrition and suckling interact to sup- press LH pulse frequency.

The effects of undernutrition on postpartum reproductive activity of sheep has received little attention. This is probably because ewes normally lamb in the spring, a time when they enter a period of seasonal anestrus. The effects of under- nutrition on postpartum reproduction in the ewe are not as dramatic as those in cattle. Lishman et al. (1974) reported that undernutrition during an 84-d postpartum period in ewes that lambed in the autumn increased the percentage of anestrous, primiparous ewes. Because prolonged dietary en- ergy restriction impairs pulsatile LH secretion in ovariectomized ewes (Tatman et al., 1990; Thomas et al., 19901, it seems likely that severe energy restriction, perhaps initiated before parturition, would delay or prevent postpartum rebreeding of ewes.

NUTRITION AND LH SECRETION 1275

In summary, undernutrition prolongs postpar- tum anestrus in cattle through several possible mechanisms, including impaired ovarian response to LH, reduced pituitary responsiveness to LHRH, and reduced pulsatile release of LHRH. The effects of undernutrition on postpartum rebreeding in the sheep have not been described adequately but may not be of practical importance for ewes that lamb in the spring.

Mechanisms Linking Luteinizing Hormone Secretion to Nutritional Status

The reduction in LH pulse frequency observed during dietary energy restriction is dramatic and probably represents one of the most important means by which undernutrition impairs reproduc- tive activity in female animals. The previous discussion emphasized the possibility that the inhibitory effects of low nutrition on LH secretion involve central mechanisms controlling LHRH secretion by the hypothalamus. We know very little about how an animals informs its central nervous system of its nutritional status and how this information is transduced into a neuroendo- crine signal. Previous work has highlighted the importance of energy reserves in determining reproductive activity. There are several hypothe- ses to explain how energy reserve might regulate LH secretion.

Body Fat. Results from early studies done with humans were interpreted to indicate that menarche occurred at a critical level of body fatness (Frisch and McArthur, 1974). This conclu- sion gave rise to the hypothesis that body fatness somehow regulates reproductive activity. This hypothesis was critiqued thoroughly in a recent review by Bronson and Manning (1991). Results from studies done with rodents clearly demon- strated that puberty did not occur at a common level of body fatness (Glass et al., 1979; Hansen et al., 1983; Perrigo and Bronson, 1983; Bronson, 1987). Puberty does not seem to occur at a constant percentage of body fatness in heifers (Brooks et al., 1985). However, changes in body fatness have been associated with changes in reproductive activity in cattle. Body fatness at calving is inversely corre- lated with interval between parturition and return to estrus (Randel, 1990). Animals that lost body fat during the early postpartum period exhibited lower basal concentrations of LH than those that maintained their body weights (Rutter and Randel, 1984). Several reports have emphasized the use of body condition score (an estimate of body fatness) at calving to predict onset of reproductive activity (Dziuk and Bellows, 1983). Because weight loss in adult animals is primarily due to a loss of fat

(Parnetto, 19641, it seems that the reduction in LH pulse frequencies associated with prolonged die- tary energy restriction (Richards et al., 1989; Tatman et al., 1990) is associated with a reduction in body fatness. In spite of these relationships between LH patterns and degree of body fatness, it is doubtful that body fat per se links nutritional status to LH release. There is no known neuroen- docrine pathway linking body fat to LHRH release. Furthermore, the complexity of the biochemical and endocrine control of nutrient absorption and metabolism implies that numerous mechanisms may be involved. It seems likely that metabolic changes resulting from changes in nutrition and parallel changes in body fatness somehow regu- late pulsatile LH release. These metabolic changes may influence LH release via specific blood-borne signals such as metabolites and(or1 metabolic hormones (Steiner et al., 1983). Alternatively, changes in nutritional status might alter availabil- ity of metabolic fuels that are necessary to maintain activity of neurons controlling LHRH release (Schneider and Wade, 19891.

Metabolic Signals. Because nutritional status influences intermediary metabolism, it seems pos- sible that nutrition may influence LH secretion via blood-borne signals that reflect metabolic status. Steiner et al. (1983) were the first to propose that circulating concentrations of insulin, certain amino acids, and nonesteflied fatty acids (NEFAI act as such signals. In general, periods of low nutrition are associated with a decrease in insulin secretion by the pancreas (Bassett et al., 19711, elevated concentrations of NEFA (Gill and Hart, 19811 due to enhanced lipolysis and reduced lipogenesis, and changes in circulating concentra- tions of various amino acids (Bergen, 1979). Few studies have attempted to evaluate the effects of metabolic hormones and metabolites on LH pat- terns in ruminants. During the past several years, my laboratory has begun to test the hypothesis that insulin and tyrosine ("'YR) enhance, whereas NEFA inhibit, pulsatile secretion of LH in young sheep (Figure 2).

Insulin may serve as a nutrition signal influenc- ing LH release. Peripheral concentrations of insu- lin are directly proportional to level of feed intake in ruminants (Bassett et al., 1971). In addition, insulin passes the blood-brain barrier to influence various functions in the central nervous system (Oomura, 1976; van Houton et al., 1979; Duffy and Pardridge, 1987; Wallum et al., 1987). There is little information regarding the effects of insulin on LH secretion. Systematic infusion of insulin in heifers did not influence patterns of LH during the estrous cycle (Harrison and Randel, 1986). Hileman et al. (1990) tested the hypothesis that the increase in LH secretion seen during ad libitum feed intake of

1276 SCHILLO

1 DIETARY ENERGY I

NE,,\ 1 INSULIN ,,/ TYRLNAA

L .1 d LHRH PULSE GENERATOR

A LHRH

Figure 2. Hypothesis for explaining how certain metabolites and insulin might act as nutritional signals that regulate pulsatile release of luteinizing hormone- releasing hormone (LHRH). Level of dietary energy influences turnover of lipids and amino acids in adipose and muscle tissue, as well as insulin secretion. Nones- terified fatty acids (NEFA), insulin, and tyrosine ("YR) may influence the LHRH pulse generator. The ability of TYR to enter the central nervous system is dependent on its concentration relative to other large neutral amino acids (LNAA).

previously underfed lambs (Foster and Olster, 1985) is due to a rise in insulin. Short-term infusion of insulin into the cerebroventricular system of ovariectomized lambs failed to elevate LH during underfeeding and inhibited LH release during ad libitum feed intake suggesting that insulin may not act as a mediator of the effects of nutrition on LH release. Alternatively, failure of insulin to stimulate LH release in underfed lambs may be due to insufficient duration of infusion, administra- tion of inappropriate doses, or failure to provide other nutritional signals that interact with insulin to influence LH release. Therefore, additional studies are necessary to more fully evaluate a possible role for insulin in the regulation of LH secretion.

Results of several previous studies (Gill and Hart, 1981; Peters, 1986; Waghorn et al., 1987) indicate that level of feeding is inversely related to circulating concentrations of NEFA. Recently, Canfield and Butler (1991) noted that circulating levels of NEFA were high when reproductive activity of lactating dairy cows was impaired. Based on these types of relationships Estienne et al. (1989, 1990) proposed that NEFA may inhibit LH release during periods of inadequate nutrition and evaluated the effects of NEFA on patterns on LH in ewes and peripubertal lambs after ovariectomy. In both cases, infusion of lipid for 8 h elevated circulating concentrations of NEFA to levels exhib- ited by fasted sheep and inhibited frequency of GH

pulses but had no effect on pattern of LH. These observations indicate that NEFA can influence neuroendocrine function but do not act as modula- tors of LH secretion in sheep. The effects of long- term administration of lipids on LH patterns has not been determined.

Some evidence suggests that availability of certain amino acids might also be involved with mediating the effects of nutrition on LH release. Preliminary studies (Bucholtz et ai., 1988; Foster, 1988) demonstrated that i.v. infusions of glucose and amino acids, either alone or in combination, maintained a high level of LH release in ovariecto- mized lambs subjected to restricted feeding. Whether these effects were due to general effects of amino acids on energy metabolism or to specific actions of certain amino acids on neuroendocrine function has not been determined. Recent evi- dence suggests that availability of TYR may be important in determining reproductive activity. Ratio of TYR to other large neutral amino acids (LNM) in sheep is decreased during fasting compared with the fed state (Koenig and Boling, 19811. Because brain uptake of a LNAA such as TYR is dependent on the ratio of that amino acid to other LNAA (Pardridge, 19831, brain levels of TYR should be higher in well-fed animals than in underfed animals. Acute administration of TYR induced onset of puberty and increased litter size in rats (Hammerl and Russe, 1987a; Hammerl and Muller, 19881, increased litter size in pigs (Ham- mer1 and Russe, 1987b1, and induced follicular growth, estrus, and ovulation in acyclic dairy cows (Hammerl, 1986). A possible mode of action is stimulation of pulsatile LH release via increased production of catecholamine neurotransmitters that might enhance LHRH secretion. Norepinephrine may stimulate LHRH release in rodents and monkeys ( K a k a and Kalra, 1983; Terasawa et al., 1988). Enhanced availability of TYR increased production of dopamine (DA) and norepinephrine in the central nervous systems of rodents (Gibson and Wurtman, 1978; Gibson, 1986; During et al., 1989). In addition, systemic injections of TYR suppressed circulating concentrations of prolactin in chronically reserpinized rats (Sved et al., 19791, presumably by enhancing production of DA, the prolactin-inhibiting hormone. Hall et al. (1990) recently studied the effects of chronic administration of TYR on patterns on LH in ovariectomized, feed-restricted lambs. Animals al- lowed ad libitum access to feed and those main- tained on a restricted diet and given abomasal infusions of TYR for 22 d exhibited elevated concentrations of this amino acid in the circula- tion and hypothalamic tissue compared with un- derfed animals given infusions of water. In addi- tion, there w&s a high linear correlation between

NUTRITION AND

concentrations of TYR in plasma and in hypothal- amic tissue. Mean frequencies of LH pulses were higher in well-fed animals than in feed-restricted animals given infusions of water. Pulse frequen- cies of LH in feed-restricted animals receiving abomasal infusions of TYR were intermediate to those of the other two groups. In addition, TYR increased the number of animals exhibiting an increase in LH pulse frequency compared with underfed animals infused with water. These results suggest that TYR may enhance LH release, but it is not the only mediator of the effects of nutrition on LH secretion in the lamb.

The importance of GH and insulin-like growth factor-I (IGF-I) in control of intermediary energy metabolism suggests that these hormones may play roles in mediating the effects of nutrition on reproductive activity. Restriction of feed intake in ruminants increased circulating concentrations of GH (Breier et a]., 1986; Foster et al., 1989; Thomas et al., 1990) and reduced concentrations of IGF-I (Breier et al., 1986; Rutter et al., 1989). Rutter et al. (19891 reported that circulating concentrations of IGF-I in postpartum cows were correlated posi- tively with body condition and increased after calf removal. These relationships imply that IGF-I concentrations might be inversely related with duration of the postpartum anestrous period. Recently, Richards et al. (1991) reported that circulating concentrations of LH and IGF-I decrease during feed restriction in nonpregnant, nonlactating cows and suggested that these responses may be linked physiologically. Studies from my laboratory failed to demonstrate an effect of GH on reproductive activity in beef heifers. Long-term treatment with recombinant DNA-der- ived GH during the prepubertal period did not influence onset of puberty, growth of ovarian follicles, or patterns of LH in heifers maintained on two levels of dietary energy (McShane et al., 1989; Hall et al., 1990).

At this time no conclusions can be made regarding the existence of specific nutritional signals controlling LH secretion. Although changes in nutritional status are associated with changes in circulating concentrations of insulin, certain amino acids, and NEFA, there is currently no strong evidence to support roles for insulin and NEFA in controlling LH release. Tyrosine, howev- er, may act together with other nutritional signals to regulate LH secretion. Because it is possible that two or more signals interact to influence LH release, it may be useful to evaluate combinations of metabolites andlor) metabolic hormones on patterns of LH.

Availability of Metabolic Fuels. The amount of time required for undernutrition to inhibit repro- ductive activity seems to be dependent on the size

LH SECRETION 1277

of an animal's energy reserves (i.e., fat). A 2-d fast blocked estrous cycles immediately in lean hamsters but had no effect in obese hamsters (Schneider and Wade, 1989). This type of relation ship may explain why a minimum body condition score at calving is necessary to ensure that cows return to estrus within a reasonable postpartum period (Dziuk and Bellows, 1983; Randel, 1990). These observations may indicate that availability of energy substrates regulates reproductive activ- ity. In support of this hypothesis, Schneider and Wade (1989) demonstrated that blockade of glycol- ysis and fatty acid oxidation resulted in immediate cessation of estrous cycles in obese hamsters. Blockade of either metabolic pathway separately had no effect on estrous activity. Given the importance of pulsatile LH secretion in control of reproductive activity, it seems plausible to propose that availability of oxidizable metabolic fuels may regulate hypothalamic control of LH release. Figure 3 summarizes a hypothesis explaining how metabolic fuels might influence LHRH secretion. During times of adequate nutrition, the major energy substrate utilized by the central nervous system is glucose (Owen et al., 1967). However, if dietary energy is restricted, then NEFA are mobi- lized from adipose tissue and are oxidized by the liver and other tissues. This results in production of ketones, which are readily utilized by the central nervous systems of nonruminants (Owen et al., 1967). Certain amino acids (valine, leucine, isoleucine) can be oxidized by the brain (Felig, 19751, whereas others contribute to pools of energy substrates by providing carbon skeletons for gluconeogenesis or ketogenesis (Bergman and Heitman, 1978). There is a paucity of information concerning brain metabolism of energy substrates in ruminants. Pel1 and Bergman (1983) estimated brain uptake of various metabolites in sheep during fed and fasted states. They detected only a small increase in uptake of ketones during fasting and concluded that brains of ruminants are much less dependent on these substrates than brains of nonruminants during period of short-term hypoglycemia. It is important to note that their method of estimating brain uptake of metabolites would not have reflected regional differences in metabolite utilization. Uptake of ketones by brain tissue is limited by permeability (Hawkins and Biebuyck, 1979) and is therefore greatest in areas devoid of a blood-brain barrier. Therefore, some areas of the brain may be more dependent on ketones than others during periods of reduced food intake. If availability of metabolic fuels rather than presence of a specific metabolite is important in regulating LHRH release, then either glucose, amino acids, or ketones should sustain LH secretion during energy restriction.

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- (RWN/

I

KETONES GLUCOSE

J. LHRH

Figure 3. Hypothesis for explaining how different energy substrates are utilized by the luteinizing hor- mone-releasing hormone (LHRH) pulse generator. Dur- ing times of adequate dietary energy, propionate is utilized for production of glucose, the major energy substrate used by the brain. During times of limited energy intake, nonesterified fatty acids (NEFA) are mobilized by fat tissue and oxidized by the liver, resulting in production of ketones. The central nervous system then uses ketones as energy substrates. Amiio acids can also be mobilized and oxidized by the brain or metabolized to form glucose and(or} ketones. The LHRH pulse generator may detect total energy available rather than specific metabolites.

Several studies done with cattle and sheep have evaluated effect of altered metabolic fuel availabil- ity on LH patterns. Perhaps most familiar are those dealing with the effects of altered propio- nate:acetate production ratios by ruminal mi- crobes. Addition of ionophores to high-roughage diets or elevating the concentrate:roughage ratio elevates propi0nate:acetate ratios in beef heifers and reduces age at puberty without necessarily influencing average daily gains (Mosely et al., 1977; McCartor et al., 1979). Because propionate is the major gluconeogenic substrate in ruminants (Trenkle, 19811, the effects of this VFA on reproduc- tion are probably attributed to increased availabil- ity of glucose. Elevated propi0nate:acetate ratios are associated with enhanced LHRH-induced re- lease of LH (Randel and Rhodes, 1980; Rutter et al. 19831, magnitude of estrogen-induced LH surges (Randel et al., 19821, and ovarian responsiveness to gonadotropins (Bushmich et al., 1980). Effects of propionate on pulsatile patterns of LH have not been reported. However, the effects of glucose on pulsatile release of LH have been investigated. Intravenous infusion of glucose did not influence LH patterns in ewes and cows maintained on adequate planes of nutrition during the postpar-

tum period (Rutter and Manns, 1986; McCaughey et al., 1988). McClure et al. (1978) blocked estrus and ovulation in cows via constant i.v. infusion of 2-deoxy-D-glucose I2DG) an inhibitor of glycolysis. Infusion of 2DG reduced the magnitude of estro- gen-induced surges of LH but did not influence LHRH-induced release of LH (Crump et al., 19821 in anestrous sheep. Induction of hypoglycemia by phlorizin, a drug that causes glucosuria, reduced amplitudes of LH pulses during the follicular phase of the estrous cycle (Rutter and Manns, 19881 and during the postpartum period (Rutter and Manns, 1987) of beef cows without affecting LHRH-induced release of LH. Together, these results suggest that reduced glucose availability reduces amplitude of LH pulses, presumably by action at the level of the central nervous system.

It is important to note that the effect of glucose restriction on LH patterns is much different from the effects of dietary energy restriction Inade- quate nutrition causes a reduction in frequency of LH pulses, whereas glucose restriction reduces LH pulse amplitude. Perhaps undernourished animals experience a greater deprivation of energy sub- strates than those given d r u g s to reduce glucose availability. Animals treated with 2DG or phlorizin apparently mobilize and metabolize fatty acids (Rutter and Manns, 1987, 1988) :and would there- fore generate ketones that could be used by neurons to sustain pulsatile LH release. This hypothesis is supported by results of recent experi- ments. Clarke et al. (1990) reported that insulin- induced hypoglycemia completely blocked pulsa- tile release of LH for several hours in ovariecto- mized ewes, This effect couldl be attributed to inhibitory effects of stress on neuroendocrine function. However, insulin-induced hypoglycemia would have deprived the brain of appreciable amounts of glucose and ketones because insulin promotes uptake of both glucose and fatty acids by peripheral tissues ITTrenkle, 1981). The inhibition of pulsatile LH release could therefore be due to deprivation of energy substrates. In an attempt to test this hypothesis, my laboratory has recently begun to investigate the effec:ts of pharmacologic blockade of glycolysis and fa,tty acid metabolism on pulsatile release of LH in ovariectomized lambs (Hileman et al., 1991). In a preliminary study, continuous i.v. infusion of 2DG for 12 h did not influence patterns of LH. We reasoned that the failure of 2DG to influence LH release was because animals had mobiliz,ed and oxidized lipids to provide energy to sustain pulsatile LH secre- tion. In a subsequent experiment, ovariectomized lambs were treated with 2L-G for 18 h, but were given an injection of methyl palmoxirate (a blocker of fatty acid oxidation; Kiorpes et al., 1984) at 10 h, a time by which animals had presumably begun

NUTRITION AND LH SECRETION 1279

mobilizing fats. This combination of drugs com- pletely abolished pulsatile LH secretion. This effect did not seem to be a nonspecific effect on pituitary function because patterns of GH were not affected by these treatments. Based on these findings, it can be hypothesized that neurons controlling pulsatile release of LH may be sensi- tive to the availability of oxidizable metabolic fuels. We do not know whether the responsive neurons are LHRH neurons or cells that regulate LHRH-producing cells.

Implications

The inhibitory effects of dietary energy restric- tion on reproductive activity of ruminants is well documented. An important mechanism for these effects seems to be disruption of pulsatile luteiniz- ing hormone [LH) secretion which results in reduced growth of ovarian follicles and anestrus. Dietary energy apparently influences LH release by affecting central mechanisms controlling lutein- izing hormone-releasing hormone (LHRH) release. Substances that mediate the effects of nutrition on LHRH release have not been identified, but recent evidence suggests that neurons controlling pulsa- tile release of LHRH are responsive to availability of metabolic fuels. Progress in understanding how metabolites influence LHRH secretion would be greater if more were known about neurons control- ling LHRH release and how energy metabolism within neurons is linked to generation of neuroen- docrine signals.

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