Suckling and the Control of Gonadotropin Secretion

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Knobil and Neill’s Physiology of Reproduction, Third Edition edited by Jimmy D. Neill, Elsevier © 2006

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46

Suckling and the Control of Gonadotropin Secretion Alan S. McNeilly The Rat, 2512 Estrus and Ovulation, 2512 Ovarian Activity, 2513 Pattern of Gonadotropin Secretion, 2514 Role of Ovarian Steroids and Opioids, 2515 Prolactin and Energy Balance, 2516 The Pig, 2516 Estrus and Ovulation, 2516 Ovarian Activity, 2517 Gonadotropins, 2517 Induction of Ovulation during Lactation, 2518 Prolactin, Opioids, and Nutritional Status, 2519 The Sheep, 2519 Estrus, Ovulation, and Gonadotropins, 2519 Prolactin, 2521 The Cow, 2522 Estrus and Ovulation, 2522 Ovarian Activity, 2522 Gonadotropins, 2523

Luteinizing Hormone, 2524 Response to Estradiol and Ovariectomy, 2524 Induction of Ovulation, 2525 Role of Prolactin, Opioids, and Negative Energy Balance, 2525 Nonhuman Primates, 2526 Ovarian Activity, 2526 Gonadotropins, 2526 Prolactin, 2528 Humans, 2528 Ovarian Activity, 2530 Gonadotropins, 2531 Luteinizing Hormone, 2531 Prolactin and Suckling, 2532 Influence of Nutritional Status, 2533 Mechanisms of Suckling-Induced Ovarian Inactivity, 2533 References, 2536

In all mammalian species the principal role of lactation is to supply the developing young with nutrition in the form of milk. However, in many (but not all) species, it also plays a major role in their reproductive strategy. In some species, such as the rat, ovulation occurs in the immediate postpartum period, but suckling causes a delay in implantation if conception occurs. In other species (e.g., the marmoset), lactation appears to have no influence on the resumption of ovulation; however, in Old World primates

and humans, suckling can induce prolonged periods of ovulatory failure and infertility. In general, in lactation the alteration in reproductive activity is caused by the suckling stimulus suppressing gonadotropin (principally luteinizing hormone) secretion and preventing normal follicular development and ovulation. However, the strategy adopted by different species is sufficiently diverse that a review of the role of suckling in controlling gonadotropin secretion can only be tackled initially

Medical Research Council Human Reproductive Sciences Unit, University of Edinburgh Centre for Reproductive Biology, Edinburgh, U.K.

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2512 / CHAPTER 46 be determined whether there are similarities in the mechanism of suckling-induced suppression of gonadotropin secretion that would suggest the involvement of a common underlying mechanism. In some species the energy burden of producing sufficient milk for growing offspring in later lactation results in a period of negative energy balance which influences gonadotrophin secretion and enhances the effects of the suckling stimulus (Fig. 1). In other species this effect seems to be very limited and suppression of gonadotrophin secretion appears to relate mainly if not solely to the direct effects of suckling alone. Whether, and at what point, in lactation these influences concur is variable across species, but it appears that the central mechanism through which the suppression of gonadotropin-releasing hormone (GnRH) pulsatile secretion occurs may be common, and will be discussed at the end of the chapter.

Hyperphagia Decreased GnRH Negative energy balance

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FIG. 1. Schematic of the effect of suckling on GnRH and gonadotrophin secretion, and hyperphagia, illustrating the direct effects of the neural suckling stimulus transmitted up the brain stem and the indirect effect through the influence of negative energy balance associated with the production of milk. The approximate timings of the changes in influence of these direct and indirect components throughout lactation are shown for the rat. [Adapted and modified from (72).]

THE RAT by reviewing the changes during lactation in representatives of the different species. Lactation is associated with a suppression of fertility in a number of species other than those reviewed in detail. However, data on the changes in prolactin and gonadotropin levels and ovarian activity are almost absent and preclude any detailed discussion in this chapter, in which the principal aim has been to evaluate the effect of suckling on gonadotropin release. At that point it can

Non Lactation

Estrus and Ovulation The time course of events in the postpartum period in the rat is illustrated in Fig. 2. Whether lactation occurs or not, a postpartum estrus occurs within 24 hours of birth, with the exact timing of onset depending on the time of parturition but not of photoperiod (1–3). The characteristics of this estrus are similar to the estrous period of the cycle (1),

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FIG. 2. Changes in the onset of estrous behavior (black box), implantation and birth (open box), the levels of progesterone secreted by the corpus luteum of pregnancy (black circular symbol), and the levels of progesterone formed at the postpartum estrus (white circular symbol) occurring within 24 hours of parturition in nonsuckled and lactating rats. Note that the corpus luteum of pregnancy regresses if the rat is not suckled but is maintained if lactation occurs.

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although more ejaculations at mating appear to be necessary for pregnancy to occur postpartum than during the estrous cycle (4). It is probable that, in the natural habitat, postpartum estrus is the normal time of conception for female rats (5), thus allowing the female to be pregnant with the next litter while nurturing the first (6). Thus when one litter is weaned the second litter is delivered shortly thereafter and a third is conceived. However, to achieve this timing, implantation (which normally occurs on day 5 of pregnancy) is delayed until around day 10, a delay of 5 to 7 days during which the blastocysts enter a metabolically quiescent state (7). Pregnancy is thus extended during lactation such that weaning occurs around days 25 to 28 prior to parturition, with pregnancy having been extended from its normal 21 days to 28 to 30 days or longer. If mating does not occur, then normal estrous cycles resume, with the second estrus occurring 4 to 5 days after the postpartum estrus. In contrast, estrus and ovulation are delayed during lactation for about 20 days in rats suckling 6 to 10 pups (8–11). The duration of this delay is dependent on the litter size (8,9), with the time interval between parturition and estrus varying between 13 and 36 days in rats with litters of between 1 and 24 pups (Fig. 2) (12). The effect of variations in litter size up to the normal maximum litter size of 13 is relatively small (8,9,12), and it is a common finding that ovulation will occur in late lactation even if attempts are made to keep the suckling stimulus at a maximum (12). However, with large litters (>12 pups), in which suckling avidity of individual pups is greater than normal or in which the avidity of suckling of a normal-sized litter (e.g., 12 pups) (Fig. 3) is maintained by providing the mother every day with a 24-hour food-and-water-deprived litter of the age corresponding to the lactational age of the mother, then the onset of estrus can be delayed for a considerably longer period (Fig. 3) (12). Thus the suppression of estrus during lactation in the rat is directly related to the strength or avidity of the suckling stimulus.

Ovarian Activity Ovulation occurs within the first 24 to 36 hours after parturition (1,2), and the resulting corpora lutea (CL) are maintained throughout lactation (8,63). The weight of these increases to a plateau around day 10 of lactation, coinciding with an increase in the secretion of progesterone from these CL and a concomitant increase in plasma levels of progesterone to reach maximum levels of 60 to 150 ng/ml by days 6 to 8 lactation (7,9,13–17). The CL of pregnancy are also maintained through lactation, but both their weight

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FIG. 3. The effects of litter size (A) and suckling activity (B) on the interval (mean ± SEM) between parturition and first estrus in the rat. Note that increasing the litter size extends this interval (A), and for a given litter size it can also be extended if suckling activity is maintained through lactation either when newborn litters of 12 pups are given to lactating rats every 7 days (B; open bars) or when litters of 12 pups of the age corresponding to the lactational age of the mother and deprived of food and water for 24 hours were given to her each day, starting on day 5 of lactation (closed bars). [Redrawn from (12).]

and progesterone output decrease, and they are only about 20% as active as the CL of lactation (17). As in nonlactating pregnant or pseudopregnant rats, the CL, at least in early lactation, are dependent on prolactin for the maintenance of progesterone secretion (9,17–20). The amount of progesterone produced by the CL is also correlated with the litter size by the indirect effect of suckling intensity on the circulating levels of prolactin (15,17,21). During the second half of lactation progesterone production by the CL becomes more dependent on luteinizing hormone (LH) (22). While the CL are maintained in lactation, all large antral follicles degenerate during the first half of lactation (7,9,10,17,23–27); also, the degree of suppression of follicle growth is related to the intensity of the suckling stimulus (17). Serum or plasma levels of estradiol (16,17,25,26) and inhibin (25–27) are consistently low during this time. However, a small increase to levels similar to those during the diestrous phase of the cycle occurs around day 10 to 12 (16), about the time when implantation of embryos, an estrogen-dependent event (28), occurs to end the

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2514 / CHAPTER 46

Pattern of Gonadotropin Secretion Follicle-Stimulating Hormone In intact lactating rats, plasma or serum levels of FSH while low in the first 3 to 5 days of lactation (22,25) are equivalent to those in nonlactating rats throughout the rest of lactation (9,16,17,22,25,31,32). The pituitary content of FSH increases by day 5 of lactation to be equivalent to, and by day 10 onward generally exceeds, that of cycling female rats (17,33,34). The total amount of FSH released in vitro in response to GnRH stimulation of pituitaries from lactating and cycling females is also similar (33,34), although there was a reduced priming effect of GnRH on FSH release (34). These results suggest that the secretion of FSH is not suppressed during lactation in the rat. However, in the near absence of inhibitory products secreted by the inactive ovary, at least during the first half of lactation, it might be expected that FSH levels should be greater than those in intact cyclic rats. That this is not the case suggests a subtle deficiency in FSH release. An increase in FSH after ovariectomy or immunoneutralization of inhibin only occurred in the second half of lactation when follicle growth had resumed and plasma concentrations of inhibin were increasing (25). The increase in FSH could be blocked by treatment with inhibin but not steroids (25). Thus during early lactation, suckling alone, in the absence of inhibin from the ovary, causes suppression of FSH, presumably by inhibiting GnRH secretion (25,35). In late lactation, when GnRH secretion resumes, FSH is maintained at normal levels by the presence of inhibin secreted by follicles developing during

lactation in response to the limited increase in LH secretion occurring during the second half of lactation.

Luteinizing Hormone It is clear that until late lactation (i.e., beyond day 16) basal serum or plasma levels of LH are suppressed to around 25% of levels seen in the diestrous phase of the cycle (9,10,16,17,21–25,31–34,36–39). LH levels increase around day 20, coinciding with the decline in progesterone and increase in 20a-dihydroprogesterone levels at that time (16,17). The low levels of LH result from suppression of pulsatile secretion of LH at least to day 10 of lactation (Fig. 4) (40–43) in contrast to the normal pulsatile secretion of LH during the estrous cycle (44,45). Even the minimal suckling input of two pups is sufficient to suppress pulsatile LH secretion on day 10 of lactation (Fig. 4) (40). During early lactation the pituitary content of LH is decreased, associated with a decrease in LH-β and gonadotropin α-subunit mRNA abundance (46–48), increasing in mid-lactation to be similar to that of the diestrous female (16,17,21,31,37,49). Pituitary GnRH-receptor content (50,51) and mRNA (52) is decreased to only 10% of that in diestrous, in suckled females (50,53). The hypothalamic content of

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lactation-induced diapause. After day 16 of lactation the number of healthy antral follicles starts to increase, although this is not necessarily accompanied by an increase in serum estradiol and inhibin levels (17,25,26). As will be described later, the absence of follicular development correlates with a low level of LH. In early lactation, no or very few follicles were present that were capable of ovulating in response to a single large injection of human chorionic gonadotropin (hCG), and those follicles present had low levels of follicle-stimulating hormone (FSH) receptors (24). Responsive follicles could be induced by pretreatment for 5 days with low levels of either hCG or LH (17,22,29). Thus, the failure of follicular development appears to be directly related to a lack of LH support, since a transient increase in FSH associated with reduced negative feedback following immunoneutralization of GnRH during lactation did not affect follicle growth (30).

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FIG. 4. The basal patterns of LH secretion (A) and response to 0.4 ng GnRH injections every 50 min (B; arrows) on day 10 of lactation in intact rats with two or eight pups. Blood samples were collected every 6 to 10 minutes for 3 to 4 hours. Note the absence of pulsatile secretion and only minimal basal LH secretion in the suckled intact rats. The adequate LH response to GnRH in the rats suckled by two pups indicates that the poor pulsatile LH pattern is not due to an inability of the pituitary to respond to GnRH. The very much reduced response to GnRH in the rats suckled by eight pups reflects a reduced pituitary content of LH caused by a greater suckling-induced suppression of hypothalamic GnRH release. [Redrawn from (40).]

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GnRH may (31,51) or may not (54) be reduced in lactation but there is no release of GnRH, measured indirectly as LH, in response to the excitatory amino acids (55–57). In spite of the reduction in GnRH receptors and pituitary content of LH, the pituitary remains responsive to exogenous GnRH, which causes the release of LH both in vivo (31,40,49,58,59) and in vitro (33,34), although in both situations the amount of LH released is reduced in comparison to diestrus. The decrease in sensitivity to GnRH stimulation is illustrated dramatically in vivo where repeated injections of “physiological” amounts of GnRH (0.4 or 0.5 ng) failed to induce normal pulsatile LH release on day 10 of lactation in mothers suckling eight pups but did induce a response in those suckling only two pups (Fig. 4) (40,59). Even with larger amounts of GnRH (20–500 ng) there is a decrease, in lactating rats (58,60), in the degree of potentiation of LH release compared with that normally seen in diestrous females (61). This decrease in response to GnRH, which occurs in vitro, appears to be related to a reduction in the post GnRH receptor changes in the gonadotrope (34), but this decrease in response can be overcome by longer treatment with GnRH (59). Thus, treatment of suckling rats with pulsatile GnRH for 24 hours from day 10 of lactation resulted in a dose-dependent increase in the pituitary GnRH receptor content to levels in nonsuckling rats and a concomitant dosedependent increase in the amplitude of the pulses of LH released after each GnRH pulse (Fig. 4) (59,60). This response is similar to that seen after weaning (46–48,62), which results in a rapid increase in GnRH receptors to normal by 16 hours after weaning (46–48). In ovariectomized lactating rats the increase in GnRH receptors is accompanied by a return of pulsatile LH secretion within 12 hours after weaning, an increase in LH-β and gonadotropin α-subunit mRNA abundance by 24 hours, and a normal pattern of LH pulses after 48 to 72 hours (46,47,63). These changes are reversed if suckling resumes (63). However, in normal ovaryintact lactating rats the restoration of LH-β and gonadotropin α-subunit mRNA and content of LH in the pituitary and the resumption of normal pulsatile LH release was delayed by 24 to 48 hours due to the continued effect of progesterone from the CL of lactation on hypothalamic GnRH output after weaning (47,48). Nevertheless, follicle growth occurs and a preovulatory surge of LH and ovulation occurs within 72 hours of weaning at day 15 (24).

Role of Ovarian Steroids and Opioids In the normal estrous cyclic female a preovulatory type LH surge can be induced by the injection of

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estrogen (64,65). In lactating females such a response still occurs, but the amount of LH released is significantly reduced (21,31), as is the response to progesterone after estrogen priming (58,66). The induction of daily surges of LH, which occurs when nonlactating females are continuously exposed to estradiol (64), is also abolished (21) or severely reduced (67). The magnitude of the response to estrogen also decreases as litter size increases (21), as does the LH response to GnRH injection. Thus in the lactating rat, the positive feedback response to estrogen remains intact even though it is considerably attenuated. The relative contributions of progesterone, and other ovarian steroids and proteins, have been assessed by monitoring the responses of LH and FSH to ovariectomy during lactation. Suckling can prevent the post-castration rise in serum and pituitary levels of LH and, to a lesser extent, FSH (at least until midlactation, days 10–12) when ovariectomy is performed in early lactation (days 2–5) (25,27,30,32,63,68,69) and this suppressive effect of suckling is enhanced by increasing litter size (21). The inhibition of the LH response results from a maintained suppression of the pulsatile release of LH, at least to day 10 (40,46,48,69), associated with a failure of the normal ovariectomy-induced decrease in hypothalamic GnRH content in early lactation in the rat (70,71). When lactating mothers are ovariectomized in mid-lactation (days 10–15), suckling can reduce to 50%, but can no longer completely prevent, the increase in gonadotropins (68,69). Thus in early lactation, the suckling stimulus alone appears to be the major, if not only, component in the suppression of GnRH/LH pulsatile secretion (Fig. 4) (72). Around mid-lactation the influence of negative energy balance associated with the greatly increased nutrient, and hence milk, demand of the growing pups exerts an increasing influence, although maintained suckling remains essential (72,73). The effects of steroids, particularly progesterone, on GnRH release are mediated in part by the actions of opioids within the hypothalamus. Thus in lactation in the rat where low levels of progesterone are maintained secreted by the CL of lactation (Fig. 1), opioids might be expected to play a role. Administration of β-endorphin caused a prolonged suppression of LH release (35) and adrenalectomy-induced increases in β-lipotropin, the precursor of β-endorphin, prevented the post-ovariectomy increase in LH and FSH in lactating rats (22), indicating that the opioid pathway involved in GnRH/LH can operate in lactation. However, blockade of opioid receptors with the broad spectrum opioid antagonist naloxone had only a marginal effect on LH secretion (74–76) suggesting that opioids are only marginally involved in sucklinginduced suppression of GnRH/LH secretion.

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2516 / CHAPTER 46 Prolactin and Energy Balance In common with most mammals, lactation in the rat is characterized by elevated levels of prolactin induced by suckling (77–79), and is inversely related to low levels of LH. Thus while the neural stimulus of suckling is obviously crucial for suppression of GnRH/LH pulsatile secretion, the humoral effects of the high levels of prolactin may also play a role in the suppression of GnRH output. This concept is supported by the fact that suppression of prolactin by CB-154 after ovariectomy in early lactation resulted in an increase in LH to 50% of the level seen in nonlactating ovariectomized females, and to 100% castration levels in mid-lactation (32,68). Administration of exogenous prolactin with the CB-154 reversed these effects. Thus, prolactin alone in the absence of ovarian steroids can augment the inhibitory effects of the neural suckling stimulus in preventing the postcastration rise in LH and FSH but is most effective in the later stages of lactation, when the suckling stimulus is declining (32,39,69). This concept is further supported by the effects on estrus onset of altering prolactin at different stages of lactation. Suppression of prolactin by CB-154 in early lactation resulted in estrus occurring some 6 to 8 days later (14,36,39), whereas in mid-lactation it occurred very rapidly (39), again implying that the suppressive effects of prolactin became more important in later lactation. These responses appear to relate to the effect of CB-154 on LH, since treatment causes a rapid increase in LH in mid-lactation but has a minimal effect on LH in early lactation (36,69). In mid-lactation administration of prolactin causes a 50% reduction in the increase in GnRH receptors occurring after weaning (46), implying a direct effect of prolactin on hypothalamic release of GnRH. This appeared to be confirmed in a GnRH neuronal cell line developed after targeted oncogenesis of GnRH neurones in the mouse (80) but will require confirmation in normal GnRH neurones in the mouse and other species. The suckling stimulus remains of key importance to suppression of gonadotropin and stimulation of prolactin secretion in lactation. Changes in both LH and prolactin appear to be closely linked, since basal levels of LH only begin to rise in intact lactating mothers as prolactin levels decline. In lactating mothers separated from all their pups for 8 hours (74) or from all but one pup for 23 hours (82) between days 6 and 10 of lactation, the reintroduction of the pups and the subsequent period of suckling was accompanied by a dramatic rise in prolactin, as expected [see (77)], as well as by a rapid decrease in LH (74,82), but not FSH (74), within 30 minutes of the onset of suckling. This decrease in LH occurred when the prolactin increase was prevented by CB-154.

However, during normal lactation in the rat the secretion of LH and prolactin is not as precisely interrelated as the pup-separation studies would suggest. The suckling activity of the pups declines throughout lactation, with a considerable variation in suckling activity during each 24-hour period (9,84). Although prolactin levels were higher and LH levels were lower over a 24-hour observation period in rats suckling 10 (compared with 5) pups (9), there was no precise relationship between suckling activity and the release of prolactin and LH (9,84). Indeed, maximum levels of prolactin could occur at a time when mothers were away from the pups for up to 60% of the time, whereas alterations in LH levels did not parallel the changes in either suckling activity or prolactin (84). Thus, the effect of the normal suckling pattern during lactation in the rat on the secretion of LH and prolactin may more readily be considered as a chronic alteration in hormone secretion rather than a series of acute changes occurring with every suckling episode. There is no doubt, however, that the suckling activity of the pups is the key component in the suppression of gonadotropin (principally LH) secretion responsible for the inhibition of ovarian activity. It is also clear that by mid-lactation the metabolic load of producing sufficient milk for the growing pups induces a state of negative energy balance. This leads to maternal hyperphagia, and the associated changes in the hypothalamus appear to play a major role in amplifying the effects of suckling on maintaining the suppression of GnRH/LH pulsatile secretion (72,73). These changes will be discussed in greater detail at the end of this chapter.

THE PIG Estrus and Ovulation The domestic pig generally remains anestrous during the first 4 to 6 weeks of lactation, and weaning the litter usually leads to estrus and ovulation within 3 to 10 days. The interval from weaning to estrus is negatively related to the number of piglets nursed (85); it also decreases with longer lactations, probably because of the reduction in suckling of older piglets (86–88). Reduction of the suckling intensity by separating piglets from sows for various periods (6–12 hours) each day from the second to third week of lactation (partial weaning) usually results in the occurrence of estrus during lactation in a high proportion of sows (89–94). Split weaning, where a proportion of the litter is weaned early, can also increase the percentage of sows exhibiting estrus by 5 to 10 days after weaning (92,94–97). These results clearly emphasize the important role of suckling intensity

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Ovarian Activity During the period of anestrus (up to 4 weeks postpartum), ovarian follicular development is characterized by a large population of small-sized follicles, and a small population of medium-sized follicles, but few large follicles (100,106–112). No CL other than those present throughout pregnancy are present, and plasma levels of both estradiol and progesterone are consistently low throughout the lactational period (113–119). During lactation the CL of pregnancy regress and rapidly lose the ability to secrete progesterone and relaxin (120), the latter related to a loss of relaxin mRNA expression (121). The number of ovarian antral follicles does not change during lactational anestrus; however, there is a gradual increase in the size of follicles, with a concomitant decrease in atresia (109,110,122). During lactations of up to 8 weeks in duration, follicles rarely exceed 6 mm in diameter (109,110), with the largest preovulatory follicle in the normal estrous cycle being 7 to 10 mm [see (123)]. Weaning results in a rapid increase in the number of medium- and largesized follicles, accompanied by a corresponding depletion of small-sized follicles (108,11,122). In the pig, FSH appears to stimulate follicle development up to 5 to 6 mm, whereas LH is necessary for the final stages of follicle maturation and ovulation (124). The lack of follicular development during lactational anestrus appears to be due to a lack of LH stimulation since growth of large follicles occurs when pulsatile LH secretion is induced by pulsatile GnRH treatment (125).

Follicle-Stimulating Hormone During lactational anestrus, pituitary levels of FSH return to normal soon after parturition (100,106,126), whereas plasma levels of FSH increase

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gradually throughout lactation (101,114,118,126). The release of FSH in response to GnRH remains constant and normal throughout lactation (114,116). Ovariectomy during lactation results in a normal increase in plasma levels of FSH (114). Since the low levels of plasma estrogen are unchanged by ovariectomy, it appears that FSH secretion is inhibited in lactation mainly by the secretion of inhibin, or other nonsteroidal products, by the ovary (114). However, suckling does reduce FSH output, even though this may be a marginal effect, because plasma levels increase significantly after weaning (Fig. 5) (117,118,122). Weaning of litters at 3 weeks (compared with 5 weeks) resulted in lower levels of FSH 2 to 3 days after weaning (118). The peak level of this post-weaning increase in FSH appears to correlate with the ovulation rate of the subsequent ovulation, but the level of FSH is not related to the interval between weaning and ovulation (117). There is an inverse relationship between FSH and LH after weaning in late lactation, with FSH levels declining as LH pulse frequency increases (127). This decrease in FSH probably relates to an increase in inhibin production by follicles developing in response to the increase in LH (128).

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on the duration of anestrus, although anestrus can be maintained throughout early lactation with as few as one or two piglets suckling (98,99). A proportion of the delay is due to the time taken for the hypothalamic–pituitary–ovarian axis to recover from the effects of pregnancy (100–102). In the absence of suckling, the first ovulation in the majority of sows occurs around 17 ± 7 days (103), although abnormal ovarian function often occurs up to 6 weeks after early weaning (104,105). In some sows removal of the piglets at birth results in immediate follicular development, estrogen secretion, and behavioral estrus (104).

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FIG. 5. Plasma levels of LH, FSH, and prolactin in two sows weaned around 21 days postpartum and with a subsequent weaning-toestrus interval of (A) 4 days and (B) >11 days. Samples were obtained at 15-minute intervals. Note that before weaning pulsatile release of LH occurred with the frequency being greater in the sow with the earlier onset of estrus postweaning. After weaning, LH pulsatile release and FSH increase, while prolactin levels decline. [From (94).]

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2518 / CHAPTER 46 Luteinizing Hormone Pulsatile LH secretion continues during pregnancy, acting to maintain CL function (98). At parturition in a number of sows high-amplitude pulsatile secretion of LH, equivalent to that occurring after ovariectomy, continues for up to 48 hours before declining and becoming completely suppressed as suckling intensity increases (101,129). Thereafter, in contrast to FSH, pituitary levels of LH remain suppressed throughout the first 3 to 4 weeks of lactational anestrus (100,106,122), basal levels of plasma LH remain low (98,112,114,118,119,122,130–132), and neither plasma nor pituitary levels of LH increase in response to ovariectomy performed before the third week of lactation (106,114). As with FSH, serum LH levels increase beyond the third week of lactation in both intact (114,133,134) and ovariectomized (114) sows and a similar increase in pituitary LH release occurs in response to GnRH (114,135,136). The suppression of serum levels of LH appears to be less in sows suckling small litters (2–4 piglets) as opposed to normal-sized litters (7–12 piglets), while there is greater suppression in sows with a long suckling duration (119); however, LH levels were still lower than normal (99). The decrease in basal LH is directly related to a decrease in the pulsatile secretion of LH, which is either absent (98,131) or very infrequent (101,112,118, 119,127,137–140) during early lactation. Treatment with the excitatory amino acid N-methyl-D,L-aspartic acid increases GnRH-driven LH secretion in sows at this time, indicating that suckling was reducing the ability of the hypothalamus to release GnRH (100,126,141). Treatment of sows with low dose estradiol between days 24 and 27 of lactation abolished endogenous pulsatile LH secretion and caused a short-term inhibition of pulsatile GnRH-induced LH release (125) suggesting that estradiol also played an important part together with suckling, in maintaining the suppression of pulsatile GnRH/LH release. Pulsatile secretion with an interpulse interval of 2 to 5 hours was present by 21 to 24 days of lactation (117,127), and the frequency of these pulses was related to the interval from weaning to estrus, the higher frequency being correlated with an earlier estrus onset (Fig. 5), and the LH response to GnRH, but not directly to ovarian follicle activity (139). In parallel with the restoration of basal and pulsatile release of LH, the ability of estradiol to stimulate a surge of LH (which in the normally cyclic sow occurs 50 to 55 hours after the endogenous increase in estradiol) also increases during lactation. No LH response occurs on day 5 of lactation; a limited response occurs up to day 15, with a normal response returning by around day 35 (133,142,143), although

estrous behavior occurs in response to the estrogen throughout this time (143). This poor positive feedback response to estradiol in early lactation probably explains the reduced LH response and the pre-ovulatory surge to the natural and normal increase in endogenous estradiol secretion observed after the early weaning of sows around day 10 of lactation (18,144,145). A significant increase in the basal secretion of LH occurs within 8 to 12 hours of weaning, from around day 21 of lactation onward (97,117,118,127). This is due to a dramatic increase in pulsatile secretion of LH, which increases over the next 2 to 3 days (117). This increase in LH release is related to a significant increase in the pituitary content of LH (106,122) and an increase in hypothalamic content of GnRH, the levels of which were suppressed during lactation (100,122,126). The characteristics of the post-weaning pattern of pulsatile secretion of LH do not appear to correlate with the time from weaning to estrus onset, which can vary from 2 to 11 days (117). However, the increase in LH pulsatile secretion is more marked in sows with an early onset of estrus, which also correlated with a greater pulsatile secretion of LH immediately before weaning (117,127) and the LH response to GnRH before weaning (139). The occurrence of early estrus and ovulation suggests that follicles capable of ovulation were present in these sows around the time of weaning and that the higher LH pulsatile secretion may have been responsible for this enhanced follicle development, since there are no differences in FSH in early and late ovulators (117). The greater pulsatile secretion of LH in some sows during lactation may reflect a relative decrease in the suckling activity of the piglets.

Induction of Ovulation during Lactation Ovulation can be induced by the administration of gonadotropins or GnRH during lactational anestrus, but the response is affected by the duration of lactation. Ovulation rate and fertility vary greatly among treatments; this is probably related to the degree of follicular development at the time of the treatment [see (123,124)]. In general, treatment with FSH or various doses of pregnant-mare serum gonadotropin (PMSG) alone or in combination with hCG fails to induce estrus and conception during the first 5 days of lactation, but the percentage of sows exhibiting estrus and conceiving increases after the third week of lactation. The pulsatile administration, but not continuous infusion (107) of GnRH (1.5–2.0 µg/hr) for 60 (or more) hours will successfully induce the development of

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large estrogenic follicles (125), estrus and the induction of the preovulatory LH surge in most sows from day 24 of lactation onward; the percentage of sows responding has been found to decrease as treatment is started earlier in lactation (116,124). These results support the concept that failure of normal follicular development during lactation in the sow is due to insufficient pulsatile secretion of LH, which is dependent on the suckling stimulus. As this declines during lactation, the pulsatile LH secretion resumes and increases, thus allowing follicular development and, eventually, ovulation.

Prolactin, Opioids, and Nutritional Status As in the other species, lactation in the pig is associated with increased levels of prolactin, with prolactin being released in response to the suckling stimulus (97,114,115,117,125,127,145–149). Treatment with estradiol does not affect prolactin secretion in late lactation (125), but an increase in ambient temperature to 30°C results in an increased release of prolactin in response to thyrotropin-releasing hormone (TRH) (138). Treatment of lactating sows with CB-154 to suppress prolactin resulted in a small increase in LH levels (significantly less than that occurring after weaning) no change (150,151), or a decrease in LH (152). Continual treatment throughout lactation only resulted in an increase in LH in late lactation (149). There appears to be no correlation between the plasma levels of prolactin throughout lactation in the sow and plasma levels of FSH or LH (114). In addition, the acute suckling stimulus, which releases prolactin, had no significant effect on endogenous levels of LH or the LH response to GnRH (114). This suggests that prolactin per se has either only a minimal suppressive or no effect on GnRH/LH secretion (149). However, it is the possible that prolactin may modify the ovarian response to gonadotropins (153) but this effect would appear to be of minimal significance overall. Suckling appears to stimulate prolactin secretion via an opiate pathway, since treatment of lactating sows with naloxone reproducibly inhibits prolactin release (138,148,154) and morphine may increase prolactin acutely (155). However, a role for opiates in causing the suppression of GnRH and hence LH and FSH secretion is unclear. Treatment with naloxone may result in an increase in (148,154,156,157) or no effect on (138,158) pulsatile LH release and may increase FSH in late lactation (159). However, morphine decreased LH in half of the treated lactating sows, prevented the increase in pulsatile LH secretion, and delayed the onset of estrus after weaning (155). A direct inhibitory effect of β-endorphin on LH release

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from pig pituitary cells in vitro has also been reported (160). Thus the role of opiates in the suckling-induced suppression of GnRH in the sow remains unclear; any opiodergic or dopaminergic regulation of GnRH/LH secretion only appears to occur to any substantial effect in later lactation (149) possibly related to the resumption of some ovarian steroid secretion at this time. Nutritional status is clearly important in sows suckling a number of piglets. In general ovarian function and litter performance after weaning was greater in sows that had a higher body mass and in those that had lost least protein during lactation (102,161,162). However, the effects of nutrition are variable and appear to depend on the ability of individual sows to utilize energy. For instance, sows with long duration suckling were heavier and lost less weight during lactation, but had a greater suppression of the GnRH/LH axis (119). The influence of nutrition in sows requires much further work, particularly since most studies relate to commercial rearing of pigs.

THE SHEEP Estrus, Ovulation, and Gonadotropins All breeds of sheep experience a period of anestrus during long days, with the breeding season beginning as day length declines in the autumn (see Chapter 41). The time of onset of estrous cycles in the autumn, and the number of cycles during the winter (i.e., duration of the breeding season before ewes become anestrus again in response to the increasing day length in the spring), are breed dependent. In many breeds, lambing occurs in the spring, so any period of lactational anestrus can coincide with the onset of seasonal anestrus. Thus to investigate the effect of suckling and lactation on ovarian function, ewes have to be mated at the end of the breeding season or during an induced ovulation in anestrus so that they will lamb during the breeding season. Only in this way can the true effect of suckling and lactation on the resumption of ovarian activity be studied in the absence of the confounding inhibitory influence of seasonal photoperiod induced anestrus. In nonsuckled ewes, estrous cycles resume within 3 to 5 weeks postpartum (163–165) and are associated with a restoration to normal estrous cycle levels of pituitary LH (166–170), FSH (167–169), and GnRH receptor (169) content of the pituitary, a normal response to GnRH in vivo (168,169,171) and a restoration of normal levels of hypothalamic GnRH (168,169). Plasma levels of FSH (172,173) and LH (166) also return to normal, and estrus associated with ovulation and pregnancy occurs (165).

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2520 / CHAPTER 46 In ewes giving birth during the breeding season and suckling lambs, estrus may be delayed for at least 3 weeks (163–165,174–176), and some may fail to ovulate before the start of seasonal anestrus (177). This interval is variable between breeds of ewe (163–165,168,175,177). During the breeding season the pituitary content of GnRH receptors (169), LH, and abundance of mRNA for LH-β and gonadotropin α-subunits increase to normal cycle levels by day 22 postpartum in suckled ewes (Fig. 6) (176). Basal (174,176,178) and pulsatile (174,176) secretion of LH increase progressively during lactation, although the increase is slower in ewes suckling two or three lambs than a single lamb (174). The increase in LH pulse frequency is directly related to an increase in the frequency of pulsatile release of GnRH into the hypophyseal-portal vessels (176) and by day 21 postpartum both GnRH pulse frequency and amplitude

Day 3

were similar to that in the normal estrous cycle (179,180). A considerable number (62%) of GnRH pulses were not associated with pulses of LH on day 3 of lactation (176), probably due to the low pituitary content (181) and releasable pool of LHcontaining granules essential for pulsatile LH secretion (182) at this time. As lactation progressed, most (62%–78%) GnRH pulses were associated with an LH pulse (Fig. 6) (176) as pituitary levels of LH, and presumably the number of LH-containing granules in gonadotropes (182), increased. Interestingly the increase in GnRH pulses at day 3 correlated with an increase in LH and gonadotropin α-subunit mRNA before any increase in pituitary LH content (176,181). In lactating Corriedale ewes lambing during seasonal anestrus, the pituitary content of LH, FSH, and prolactin, as well as the hypothalamic content of GnRH and plasma FSH, had increased

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FIG. 6. Changes in the pituitary content of LH and the abundance of the mRNAs encoding the LH-β subunit and gonadotropin alpha-subunit in relation to the pulsatile release of GnRH (open data points) from the hypothalamus into the hypophyseal portal vessels and release of LH (closed data points) from the pituitary in suckled ewes from late pregnancy through to day 22 of lactation. Note that at term pituitary content of LH is very low related to undetectable LH-β mRNA. On day 3 postpartum pulsatile secretion of GnRH returns, but only a few GnRH pulses (*) result in the release of a pulse (*) of LH, related to the low levels of pituitary LH in releasable storage granules. The progressive increase in GnRH pulsatile release results in an increase in LH-β mRNA, LH pituitary content in the form of releasable granules, and hence release of pulses of LH from the pituitary. [From (176,181,182).]

22

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by 11 to 17 days postpartum to those in seasonal anestrus (183). However, LH pulse frequency 8 to 14 days after parturition was greater in these ewes being suckled during anestrus than in nonsuckled anestrous ewes (183), possibly related to reduced ovarian steroid feedback. The pituitary responsiveness to exogenous GnRH recovers to normal by 14 days postpartum in ewes lambing during the late breeding and early anestrous season (166,176,184). However, in spite of the normal LH response to exogenous GnRH and the increased pulse frequency of lactating ewes, seen by 14 to 20 days postpartum, only between 46% and 50% of ewes showed a positive feedback response of LH to estradiol by 30 days postpartum (177). This clearly implies an inadequacy of hypothalamic GnRH release, since the positive feedback response is dependent on GnRH (157,179,185). A similar decrease in the positive feedback response to estradiol was observed in ovariectomized lactating ewes also lambing during the breeding season (186). Indeed the pulse frequency of LH in these ewes was significantly less than that in ovariectomized nonlactating ewes (186). The depression of plasma LH following chronic estradiol treatment was also greater in ovariectomized lactating, as opposed to nonlactating, ewes; this indicates that there is a suckling-dependent enhanced sensitivity to the negative feedback effects of estradiol in the Merino ewe. Similar studies have yet to be carried out in other breeds of ewe. Ovulation can be induced in lactating anestrous ewes by the continuous pulsatile administration of low doses of GnRH. In those ewes that ovulate (86%), inadequate CL function occurs if GnRH is delivered at a constant frequency (hourly) in the absence of progesterone pretreatment (187). However, if the frequency is progressively increased (from once every 3 hours to an hourly rate), ovulation with adequate luteal function can be induced in the majority (80%–90%) of ewes, with normal luteal function occurring in most ewes, especially if pretreated with progesterone before GnRH (188). Ovulation can be successfully induced in nonsuckling anestrous ewes with either LH (189,190) or GnRH with progesterone priming (191). This indicates that absence of normal follicular development during lactational and seasonal anestrus is primarily due to an inability to generate the increase in pulsatile GnRH and hence in LH pulsatile release for the final stages of follicular development before ovulation (192). Accelerated follicle growth related to a fast increase in plasma FSH after lambing may have a deleterious effect on subsequent ovarian function, with early ovulation resulting in the formation of an inadequate CL of short duration (175). In suckled ewes the delayed increase

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in LH pulses appears to delay development of follicles such that first ovulation is usually associated with a normal CL (175). There was no difference in the number of receptors for LH or prostaglandin F2-α (PGF), the sheep luteolysin, or the number of small or large luteal cells in short compared with normal lifespan CL postpartum (193). Thus, either excess PGF continues to be released from the involuting uterus or LH support is inadequate.

Prolactin Plasma levels of prolactin are low during the breeding season, increase in response to increasing day length, and are high during the period of anestrus (194). Prolactin levels in lactating ewes, whether in the breeding season (183) or in anestrus (195,196), are greater than in nonlactating seasonally anestrous ewes, maintained by the suckling stimulus, which increases the secretion of β-endorphin (197). As in other species the prolactin response to suckling declines throughout lactation (198), as the pituitary– ovarian axis returns to normal in lactating ewes. Although these changes in prolactin suggest a possible direct role for prolactin in suppressing LH secretion, there is little evidence to support this in the ewe. Treatment of lactating ewes with CB-154 to suppress prolactin may (163) or may not (173) advance the onset of estrus postpartum but does not appear to influence the basal or pulsatile release of LH in lactating ewes (199,200), even though the release of LH to exogenous GnRH may be increased (199). It is possible that high levels of prolactin may directly reduce ovarian estradiol (201) and progesterone (202) secretion and also reduce the positive feed back effect of estradiol on LH release (196). These effects may contribute to reduced fertility of lactating ewes following the induction of estrus (203,204), although inadequate LH secretion is a more probable explanation (205,206). Resumption of pulsatile GnRH and LH release and normal FSH secretion occurs while prolactin levels are several-fold greater than in the normal estrous cycle (175,176). Prolactin receptors have been identified on gonadotropes in the sheep (207) and interactions between dopamine and prolactin on the GnRH-induced release of LH between breeding season and anestrus ewes have been identified (208). How these observations relate to changes in LH secretion during the suckling-induced prolactin release in lactation in sheep remains to be explored. Thus, there is little evidence to support a central role for prolactin suppressing gonadotropin secretion postpartum, with the principal inhibition arising from the suckling stimulus itself (209).

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2522 / CHAPTER 46 THE COW

Ovarian Activity

Estrus and Ovulation

Before first ovulation in both milked and suckling cows, plasma and milk levels of progesterone remain basal, thus confirming the absence of a functional CL (216–218,220,224,229,232,267). Plasma levels of estradiol also remain suppressed until near the time of first ovulation (217,224,229,230,268–270). This lack of steroid secretion is associated with a suppression of the final stages of follicular development prior to the endocrine changes preceding the first preovulatory LH surge (268,269,273–276). Healthy 10 mm follicles have been observed in weaned cows by 7 days, in milked cows by 10 days, and in suckling cows by 20 days postpartum (265,268,269). However, in milked cows the percentage of nonatretic follicles in animals before first ovulation decreased with time postpartum up to day 35 (275). However, in up to 20% of cows, the absence of ovulation of some of these large follicles may lead to the formation of follicle cysts associated with lower levels of progesterone (277). Ultrasound scans of the ovaries allowing tracking of follicle dynamics during lactation have shown that during the normal estrous cycle usually only one dominant follicle develops at any one time such that during the luteal phase between two and three dominant follicles grow, each regressing as a new dominant follicle develops (278–287). In milked cows a dominant follicle begins to develop within 7 to 20 days postpartum, the time being shorter in fall calving cows, and approximately 75% of these follicles ovulate (217,288). In the remainder, first ovulation is preceded by a variable number of waves of dominant follicle growth (217,283–285,288). Decreased fertility in dairy cows is associated with a prolonged time of follicle development related to reduced oocyte competence (283). In suckled cows, in contrast, although the first dominant follicle also appears at the same time as in milked cows, around 10 days postpartum, only very few (11%) of these follicles ovulate (Fig. 7) (217,289–291). The interval from calving to first ovulation is characterized by the growth and regression of a variable number of dominant follicles (Fig. 7) (229,230,289–291). Following ovulation of the first dominant follicle in both milked and suckled cows the CL is almost always short lived (217,229,230,287,289). The dominant follicle destined to produce these inadequate CL may have reduced LH receptors on the theca and granulosa cells and decreased estradiol in follicular fluid (283,285,286,292,293). Low body condition at least over the first 9 weeks reduces the number of large follicles that are estrogenic (294). It is now clear that in both milked and suckled cows dominant follicles grow and regress throughout lactational anestrus, and any delay to first ovulation relates to a failure of adequate pulsatile LH secretion to generate sufficient

In the lactating nonsuckled cow, estrous cyclicity resumes in the majority at around 30 to 70 days, but may occur as early as 20 days, postpartum (210–218). This first overt estrus is often preceded by ovulation with a lack of behavioral estrus, “silent heat,” and the formation of an inadequate CL secreting reduced amounts of progesterone for a shorter than normal period (213,214,216,217,219). Suckling can delay this interval to estrus onset for a variable time up to 150 days postpartum (210,220–231). Thus typical times to the onset of estrus would be 25 days for milked cows and 57 days for suckled ones (232). Calf removal (either temporary or permanent) or the prevention of suckling by the use of nose plates, shortens the acyclic period (233–240). The interval to first ovulation may (241) or may not (224) be increased if dairy cows are milked more frequently. Similarly, the interval to first estrus may (241,242) or may not (243–246) be extended if the number of calves suckling is increased, although restricting suckling to a limited period each day may result in an earlier return to estrus (242,247,248). Although it is clear that the interval to estrus onset in both milked and suckled lactating cows is longer than in nonlactating postpartum cows (221) and that suckling causes a longer delay than milking, there is considerable variation in the duration of this delay, an effect related to several environmental factors. Of these, photoperiod and nutrition appear to be the most important. Although cows do not display a period of seasonal anestrus, season does affect the duration of the interval to first estrus. Thus in both milked (213) and suckling (249–251) cows, those calving in late autumn and winter tend to have a longer period of acyclicity than those calving in the spring or summer (251–254), an effect that can be replicated by artificial alteration of the photoperiod (253). A parallel seasonal change in ovarian follicular development in nonlactating cows has also been reported (254), and the time from parturition to the emergence of the first dominant follicle was shorter in fall than spring calving dairy cows (217). This photoperiodic influence is also closely related to an effect of nutrition with heavier (and therefore presumed better-nourished with near normal energy balance) animals resuming estrous cyclicity early (244), with provision of increased dietary energy being associated with a reduction in the period of acyclicity (225,226,255–260). In contrast, poor nutrition resulting in a state of negative energy balance, is associated with a prolonged anestrous period (225,226,231, 259–266) and will be discussed later.

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Diameter (mm)

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FIG. 7. Patterns of growth and regression of individual follicles monitored by ultrasound and levels of progesterone (closed square) and estradiol (o) in two suckled beef cows (A) and the appearance of the pulsatile release of LH during lactation in suckled beef cows (B). Note in A that the first dominant follicle only ovulated (indicated by the arrow) in 11% of cases and a highly variable number of dominant follicles grew and regressed in the remainder before ovulation occurred. Note in B that the earlier resumption of pulsatile LH secretion in cow 211 is associated with the earlier resumption of estrous cycles, related to ovulation 21 days earlier than cow 169. [Redrawn from (230,299).]

estradiol secretion from each dominant follicle to induce a preovulatory LH surge.

Gonadotropins Follicle-Stimulating Hormone In suckled cows, pituitary contents of FSH throughout lactation are not significantly different from

those in the normal estrous cycle (260–263,267,276). After an initial increase after parturition, plasma levels of FSH remain equivalent to those in the normal estrous cycle throughout the period of lactational anestrus in both suckling and milked cows (214,216,227,245,297,299,300). In both beef and dairy cows plasma concentrations of FSH increase within 10 days of parturition and then fluctuate every 7 to 10 days in a regular wave pattern, with each increase preceding the emergence and growth of

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Luteinizing Hormone The pituitary concentration of LH at the end of pregnancy is suppressed and increases throughout the postpartum period in suckling cows, reaching levels similar to those in cyclic animals by 40 to 50 days postpartum (267,276,295–298). Plasma LH concentrations also increase throughout the postpartum period (214,217,218,230,258,259,270,289,305–309), with this increase relating to a resumption of the pulsatile secretion of LH (Fig. 7) (215,217,218,224,230, 258,259,273,302,310,311), but no change in bioactivity of LH (312). This increase is paralleled by an increase in the release of LH from the pituitary in response to GnRH both in vivo (220,304,313,314) and in vitro (276,297). These changes in LH occur more rapidly in milked cows (around day 10 postpartum) than in suckled ones (up to day 50 postpartum) (217,230,236). The major increase in LH pulsatile secretion occurs in the few days preceding the first ovulation postpartum (29,230,232,251,273,315), with suckling prolonging the nonpulsatile period. Since there is no change in either the affinity or the number of GnRH receptors in the pituitary (276,297), the absence of LH pulses is presumably due to a reduction in the hypothalamic release of GnRH. This has not been measured directly in vivo. Hypothalamic content of GnRH was greater in suckled than nonsuckled ovariectomized lactating cows (316), although in ovary-intact cows GnRH release from the stalk median eminence in vitro was not affected by weaning or level of nutrition (239). The delay in return to ovulation due to dietary restriction or negative energy balance is related to a delay in the resumption of pulsatile LH release (225,226,228,258,317). Increased dietary energy, which reduces the time to first ovulation, may not alter LH pulse frequency (258,259) but may increase LH pulse amplitude (232). The short-term infusion of insulin increased follicle estradiol production without altering pulsatile LH secretion (318) implying an effect of insulin directly on the ovary.

Response to Estradiol and Ovariectomy Although the injection of estradiol into suckled cows may induce the positive feedback release of both LH and FSH by day 17 (319), this response may be reduced in comparison to that in nonsuckling cows during the post partum period (320). In milked cows, no response to estradiol was observed on day 5, but responsiveness had returned by day 15 postpartum (321). These results further suggest that suckling directly impairs GnRH secretion in vivo. The increase in LH after ovariectomy on days 4 to 5 postpartum is delayed in cows suckled by one or two calves (315,321–323). Both basal levels and the pulsatile secretion of LH are decreased for 5 to 10 days after ovariectomy. Thereafter, both basal levels and pulse frequency of LH increase throughout the postpartum period, and levels are similar to those of nonsuckled ovariectomized cows by 40 to 60 days postpartum (315). This escape from the inhibitory effect of suckling can be further delayed if the ovariectomized suckled cows are treated with estradiol, when the increase in LH can be prevented for up to 72 days (Fig. 8) (322,323). In contrast to the inhibitory effects of suckling on the post-ovariectomy rise in LH, the increase in plasma levels of FSH was similar in suckled and nonsuckled cows. These results imply that in the

35 OVX weaned + E2 30 25 20 15 10 LH (ng/ml)

the next wave of dominant follicle growth (301–304) exactly as in the normal estrous cycle (283–285). The GnRH-induced release of FSH from pituitaries of suckling cows did not change throughout lactation up to 56 days postpartum (297). In contrast, the in vivo FSH response to both single large bolus injections (303,304) and small repeated injections (272) of GnRH declined with time postpartum. This probably reflects an increase in ovarian activity with the concomitant increase in secretion of inhibin and/or estradiol.

5 35 OVX suckled + E2 30 25 20 15 10 5 2

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Weeks post-calving FIG. 8. Suckling-related increase in the sensitivity to the negative feedback effects of estradiol in beef cows postpartum. Cows were ovariectomized (OVX) at parturition and implanted with estradiol (+E2). They were then either weaned or suckled. Note that E2 delays, but does not prevent, the post-ovariectomy increase in pulsatile secretion of LH in weaned cows. This increase in LH was significantly reduced if the cows were suckled. [From (323).]

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early postpartum period, when suckling is maximal, the suckling stimulus alone is sufficient to inhibit the pulsatile secretion of LH. Indeed treatment of suckled beef cows with an antiestrogen between days 20 and 30 postpartum did not affect the time to first estrus (324). However, as lactation proceeds, suckling maintains an increased hypothalamic sensitivity to the negative feedback effects of low levels of estradiol and further delays the onset of the preovulatory increase in the pulsatile secretion of LH.

Induction of Ovulation Although ovulation can be induced in postpartum cows by single intramuscular injections of GnRH, the results are very variable due to variations in the stage of follicle development at the time of the GnRH injection [e.g., see (220,283,284,325–330)]. Even if ovulation does occur it may result in an inadequate CL. Greatest success occurs when follicular development is advanced and associated with increased levels of estradiol (232,328), which will occur earlier in the nonsuckled, as opposed to the suckled, lactating cow but cannot be induced by treatment with FSH (268). A more successful treatment is the administration of frequent low doses of GnRH (311) or LH pulses alone (289), which mimics the normal increase in LH secretion in the preovulatory phase of the cow estrous cycle (283,284). Ovulation with normal luteal function can be induced in this way during the early postpartum period in suckled cows (289,299), but intermittent treatment of milked cows has yielded variable results (272,331). The results further support the concept that the failure of follicles to progress through the final stages of maturation to pre-ovulatory status and ovulation is due to a failure of the normal pulsatile secretion of LH as a result of decreased secretion of hypothalamic GnRH due to the suckling stimulus. However, in dairy cows in particular, the huge nutrient demands associated with producing high milk yields results in many instances in a negative energy balance which also has a major impact on the responsiveness of the ovaries to gonadotropins as discussed next.

Role of Prolactin, Opioids, and Negative Energy Balance As in other species, lactation in the cow is associated with high levels of prolactin (224,332), in addition to the increase in prolactin secretion associated with

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increased day length and temperature (332,333). However, plasma levels of prolactin are similar in suckled and milked cows (224,334) and in cows suckling one or two calves (335), even though there is a considerable difference in the time to onset of estrus postpartum. Furthermore, suppression of plasma prolactin concentrations with CB-154 (243,314,336,337) does not affect the time to estrus onset, and infusion of prolactin failed to affect the pattern of LH secretion (310). It therefore seems improbable that prolactin plays any active role in the suppression of ovarian activity postpartum. The role of opioids in the suckling-induced suppression of GnRH in the lactating cow remains unclear. Naloxone treatment in dairy cows did not affect LH (259) and in suckled cows had a minimal and variable effect to increase LH in early lactation (338,339), the response apparently depending on ovarian status (300). Levels of met-enkephalin were increased in the preoptic area (POA) of the hypothalamus in suckled cows with reduced energy intake regardless of suckling (239). However levels of β-endorphin in both the hypothalamus and POA were increased in suckled cows (239). While the suckling stimulus, together with calf bonding (340) is clearly the major factor in suppressing GnRH/LH pulsatile secretion leading to failure of follicles, induced to grow by the normal levels of FSH, to reach the final stages of follicle maturation and secrete normal estradiol levels, many cows are in negative energy balance during lactation. In suckled beef cows negative energy balance associated with reduced body condition leads to a smaller size of pre-ovulatory follicle, which returns to normal with better feeding (341). The situation is extreme in dairy cows, particularly those selected for high milk yield (283–285) and is associated with decreased plasma levels of leptin (342–344), insulin (286,301,318) and IGF-1 (285,342,344). Both insulin and IGF-1 act locally within the ovary to increase responsiveness to gonadotropins (283,285,344). Increased dietary input, or infusion of insulin increases ovarian responsiveness to gonadotropins without any significant effect on gonadotropin secretion (301,318). This supports the concept that in cattle at least one significant component of negative energy balance is through direct effects at the level of the ovary, acting in concert with the indirect effects of negative energy balance within the hypothalamus to affect GnRH and gonadotropin secretion. These latter effects would operate through an endocrine loop, since, e.g., leptin levels are lower in lactating cows in negative energy balance and an effect via leptin at the hypothalamus, affecting GnRH secretion probably also operates.

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2526 / CHAPTER 46 NONHUMAN PRIMATES Lactation-induced infertility has been recorded in a number of nonhuman primates, with the overt reasons for failure of conception being (a) inhibition of ovulation and (b) reduction or abolition of sexual activity. These primates include the great apes, the gorilla (345), and the chimpanzee (346–348); lesser Old World anthropoids such as the baboon (349); various species of macaque (346–348); and members of the genus Cercopithecus (349,359). Among the New World primates, an effect of lactation on reproduction has been observed in spider (360), howler (361), capuchin (362) and squirrel monkeys (363,364), a limited effect has been observed in the cotton-top tamarin (365), but none has been seen in the common marmoset (366,367). The majority of studies on the influence of suckling on gonadotropin secretion and ovulation activity have been restricted to the rhesus monkey. Thus some caution must be exercised in assuming that these changes in the hypothalamus–pituitary–gonadal axis are truly representative of nonhuman primates in general. However, sufficient similarities exist between the rhesus and cynomolgus monkey during the period of lactational infertility such that they will be discussed together.

Ovarian Activity An absence of follicular development associated with low plasma levels of estradiol (358,368,369) and inhibin (365) persists throughout most of the period of lactational infertility, up to around 150 days postpartum. Thereafter estradiol and inhibin increase as follicle growth resumes in response to increased LH secretion (358,365). In the nonsuckled monkey, normal follicle development with ovulation resumes by about 42 days postpartum, with first menses occurring about 14 days later (369). Earlier resumption of ovarian activity can be induced by appropriate gonadotropin treatment, suggesting that there is no intrinsic ovarian insensitivity to gonadotropins in the early postpartum period (370). In nonsuckled animals, plasma progesterone levels decline rapidly after parturition (358,368,371–373); this is associated with the collapse of the CL of pregnancy (368). In contrast, in lactating suckled mothers, plasma progesterone levels, while decreasing over the first days postpartum, remain significantly higher than those in the normal follicular phase of the cycle for 2 to 3 months postpartum (368,369,372). This progesterone secretion is due to maintenance of the

CL of pregnancy, as a result of the increased plasma levels of prolactin associated with lactation (372–374). Prolactin delays the functional luteolysis of the CL because it has been found that suppression of prolactin postpartum, either by weaning the infant (372) or by treating the mother with CB-154 (373,374), results in luteolysis and a decrease in progesterone secretion.

Gonadotropins Plasma levels of FSH remain suppressed during early lactation but increase progressively, becoming equivalent to follicular-phase levels by 6 to 10 months postpartum (358,372). In contrast, plasma levels of LH are suppressed for up to 9 months postpartum and only increase to normal follicular-phase levels by around 12 months (372,375). In the first month postpartum, there is no response of either LH or FSH to GnRH (376). The suppression in basal levels of both LH and FSH is paralleled by a failure of LH response and a reduced FSH response to the positive feedback effects of estradiol benzoate for the first 3 to 6 months postpartum (Fig. 9) (372–374,376–378). The response then gradually increases, thus approaching a normal positive feedback response of FSH by 7 to 9 months and of LH by 10 months postpartum (372,374). In nonsuckled monkeys, a normal response returns by the end of the first month postpartum (372). Since in the rhesus monkey (379) and the stumptail macaque (380) the positive feedback effect of estrogen is predominantly due to a direct stimulatory action at the level of the pituitary gland, these results imply that suckling has inhibited the hypothalamic release of GnRH (372). In accordance with this, the prompt rise in serum LH and FSH levels that normally follows ovariectomy is delayed for at least 30 days in postpartum females nursing infants (358,381). In suckled cynomolgus monkeys ovariectomized on day 14 postpartum, LH increased gradually but with considerable variation in both rate of increase and maximum LH concentrations reached (358). A similar reduction in serum LH and FSH, as well as inhibition of the positive feedback effects of estradiol, occurs in non-postpartum monkeys fostering neonates (Fig. 9) (372). Thus, the suppression of gonadotropin secretion is primarily due to the suckling stimulus and is not dependent on antecedent events associated with gestation and parturition (374), but ovarian products are essential for maintaining suppression of LH and FSH throughout lactation (358). In contrast, a change in opioids does not appear to be involved in the suckling-induced

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FIG. 9. Suckling-induced inhibition of the positive feedback effect of estradiol on LH and FSH release in the rhesus monkey. Estradiol benzoate was injected subcutaneously (arrows) each month postpartum in mothers suckled by their own infants (A), in mothers whose infants were weaned on the day of parturition (B), and in mothers suckled by foster infants from group B (C). Note the absence of gonadotropin responses during the initial months of nursing in both natural and foster mothers, but not in mothers weaned at the time of parturition. [From (372).] Day-time 06.00 − 18.00 Saline Prolactin (ng/ml)

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FIG. 10. Effects of naloxone and saline infusions during the daytime or nighttime on prolactin concentrations and pulsatile LH release on day 73 postpartum in nursing monkeys ovariectomized 58 days earlier. Note the rapid inhibition of prolactin secretion (mean, n = 3) during naloxone infusion but no effect on the pulsatile release of LH (individual profiles). [From (358).]

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2528 / CHAPTER 46 suppression of gonadotropins, since treatment with naloxone did not affect LH release in both ovaryintact and ovariectomized monkeys (Fig. 10) (358). The suppression of pulsatile GnRH release induced by suckling has been confirmed indirectly in the rhesus monkey by the demonstration of suppression by suckling of multiunit electrical activity (MUA) recorded in the medio-basal hypothalamus, as a measure of the GnRH pulse generator and hence a surrogate for GnRH release. Each short burst of MUA is associated with the release of a pulse of LH supporting the concept that MUA relates directly to GnRH release (382). Suckling of nonpregnant ovaryintact normally cycling foster mothers by foster infants inhibited MUA activity and LH secretion, stopping menstrual cycles, but was without effect in ovariectomized mothers (Fig. 11) (375).

Prolactin Plasma levels of prolactin are elevated throughout lactation (358,372,374). Although there is a clear increase in prolactin in response to suckling episodes when suckling frequency is low (383,384), no specific suckling-related episodes of prolactin release appear to occur during early lactation, when suckling frequency is relatively high (358,384,385). Sucklinginduced prolactin release during both the day and night time is mediated by endogenous opioids, since prolactin secretion was completely blocked by naloxone treatment (Fig. 10) (358). Injections of prolactin in bonnet monkeys have been reported to (a) reduce the LH response to GnRH (386) and (b) extend the period of lactation infertility (387). However, both basal levels of LH and FSH and the positive feedback effects of estradiol continued to be inhibited by suckling in rhesus monkeys treated with CB-154 to suppress prolactin throughout the postpartum period (374). Although the positive feedback response occurred somewhat earlier in the postpartum period (3 months) than in suckled monkeys with normally elevated prolactin levels (372), this may reflect a reduction in suckling activity of the neonates because milk secretion had been inhibited by the CB-154 treatment (374). In the rhesus monkey suckling-induced suppression of MUA activity reflecting GnRH pulsatile secretion may be interrupted by suppression of prolactin secretion by CB-154 treatment, although this effect was not universal (Fig. 11) (375). Nevertheless it does show that prolactin under some circumstances can interfere with GnRH pulse generation during suckling, but the factors which determine whether there will or will not be an effect remain to be determined (375).

The prolactin-dependent maintenance of CL function and progesterone secretion does not appear to be important in the suppression of gonadotropin secretion. The plasma levels of progesterone, which are only maintained for 2 to 3 months postpartum, are well below those required for the inhibition of gonadotropin secretion (388). However, other ovarian factors, probably estradiol, do appear to be necessary (358,381). Thus, the evidence to support a role for prolactin in the suppression of gonadotropin secretion and ovarian activity in the rhesus monkey is unclear. Indeed, lactation does not suppress fertility in the common marmoset even though prolactin levels are elevated during lactation (367). Thus, the suppression of fertility postpartum is mainly, if not exclusively, dependent on the suckling activity of the infant. Earlier conception postpartum occurs in rhesus monkey mothers, who actively encourage independent behavior of their infants by rejecting more of their infants’ attempts to suckle (389). The period of anovulation is prolonged in primiparous mothers, which may have higher suckling frequencies than multiparous mothers (390–392), although there is also evidence for an increased sensitivity of primiparous mothers to the suckling stimulus (393). Nevertheless, with the direct evidence that prolactin can influence the effects of suckling on MUA activity in the hypothalamus of foster suckled rhesus monkeys, but only when the ovaries steroids are present, it is clear that prolactin may influence GnRH/LH secretion, but the effect is apparently unpredictable, even within the same animal (Fig. 11) (375).

HUMANS Although there is no doubt that breastfeeding in women delays the resumption of ovarian cyclicity and menses, the duration of this delay is immensely variable both between and within different populations (394–424). Lactational amenorrhea may last from 2 to 3 months to 3 to 4 years, with the duration depending principally on the pattern of suckling: The more frequent or intense the suckling, the longer the delay and it is now clear from a number of studies that the lactational amenorrhoea method (LAM) encompassing full breastfeeding and amenorrhea over 6 months of lactation is a very reliable contraceptive [see (419,425)]. If women remain amenorrheic then this can be extended to 9 months of breastfeeding (423). Not only does this contraceptive effect continue to play a vital role in fertility control worldwide, breastfeeding is also associated with prevention of infant mortality and morbidity (426–429).

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FIG. 11. Changes in multiunit electrical activity (MUA) recorded from the hypothalamus, as a surrogate for GnRH release, in relation to serum levels of prolactin (PRL), LH, estradiol (E2), and progesterone (P4) in ovary intact (A, B) or ovariectomized (C) adult female rhesus monkeys which were suckled by foster infants (open bar). During this suckling period the intact monkeys (A, B) were treated for different durations with bromocriptine (closed bars) to suppress the suckling-induced prolactin release. Note that in the absence of the ovaries (C) suckling did not affect MUA activity or LH secretion even though prolactin levels were elevated. In contrast, in ovary-intact monkeys (A, B) suckling suppressed MUA activity and inhibited LH secretion leading to a suppression of ovarian E2 and P4 secretion. These changes were associated with elevated levels of prolactin. When prolactin release was suppressed with bromocriptine during the suckling period there was either no effect (A), or a resumption (B) of MUA activity. This effect was variable and in the majority of cases there was no effect of suppression of prolactin on MUA activity. [Redrawn from (375).]

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2530 / CHAPTER 46

Ovarian Activity Throughout the period of lactational amenorrhea in most women, ovarian follicular development, monitored by changes in plasma levels of estradiol (399,416,452–456) and inhibin A and B (454,455), and urinary estrogen excretion (396,408,409,454–463) as well as by ultrasonic visualization of the ovary (454–456,463), is inhibited (Fig. 12). Luteal structures never occur, and levels of urinary pregnanediol and plasma progesterone remain low throughout. Shortterm elevations in estrogen secretion lasting a few days may occur, but the maximum levels achieved are reduced in comparison to those associated with the preovulatory follicle (396,402,408,454,455,464). In contrast, in non-breastfeeding women, urinary estrogen excretion and plasma estradiol levels indicative of preovulatory follicle development resume within 20 to 30 days postpartum, and ovulation takes place within 4 to 8 weeks postpartum (396,402,457,458, 460,465,466). A proportion of women ovulate during breastfeeding, some ovulate before a menstrual period has occurred, and some will become pregnant without any intervening menses (396,402,418,467). In the majority of these cases, however, the luteal phase following ovulation is deficient but tends to improve with subsequent ovulatory cycles as lactation continues (396,399,402,409,417,418,451,461,467), a situation

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The postpartum period of amenorrhea is associated with raised levels of prolactin, and in most studies (394–397,399,400,406,407,422,430–433) the duration of lactational amenorrhea is closely correlated with this period of hyperprolactinemia. Suckling results in the release of prolactin (406,432,441), with the amount released being greater in the afternoon and night than in the morning (406,433,437,439). Both the amount of prolactin released in response to suckling and the basal levels of prolactin decrease with time postpartum and during lactation (397,399–401,406,407,43,437,439,440, 442–448) unrelated to any change in half-life (439). While the isoforms of the prolactin secreted may not change (384) the biological activity of prolactin may be increased during lactation in women (449,450) associated with prolonged lactational amenorrhea (450). This decline in prolactin levels is more noticeable in populations in which there is a relatively low frequency of breastfeeding episodes (3–5 per day) than when a high frequency (more than 10 breastfeeding episodes per day) is maintained throughout lactation. In the latter case the frequency of suckling and the inter-suckling intervals are key factors, and, although the response to suckling may be minimal, basal levels of prolactin remain elevated at all times (397,431,447,451).

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FIG. 12. Changes in the pattern of breastfeeding, urinary estrone and pregnanediol, and plasma LH and FSH, and inhibins A and B in representative breastfeeding women treated with a control (lefthand) or a low dose transdermal estradiol releasing (TES) patch (closed box) as used for HRT (right-hand). Note that while there was no effect of the TES on suckling activity, there was a dramatic suppression of both LH and FSH leading to suppression of ovarian secretion of steroids and inhibins, indicating inhibition of reduced follicle growth. These results indicate that there is an increase in sensitivity to the negative feedback effects of estradiol in early lactation in women. [Redrawn from (454).]

similar to the pattern of luteal activity during the resumption of menstrual cycles of non-breastfeeding women postpartum (459,461,465,466). The relatively high proportion of inadequate luteal phases is thought to be a principal cause of the reduced fertility of women who resume menstrual cycles while continuing to breastfeed (419). Although gonadotropin stimulation immediately postpartum (7–15 days) fails to stimulate estrogen secretion (468,469), thereafter, exogenous gonadotropin (453,470) or treatment with pulsatile GnRH to induce increases in endogenous gonadotropins (463,417) will stimulate follicular development, estrogen secretion and ovulation. Thus, the ovary remains responsive to gonadotropin stimulation throughout the period of lactational amenorrhea, although induction of ovulation with GnRH pulses may lead initially to the formation of inadequate CL (463) with a return to normal luteal function if treatment is continued (471).

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Follicle-Stimulating Hormone Plasma levels of FSH increase within 3 weeks postpartum in breastfeeding women and remain within the normal range of menstrual cycles throughout the postpartum period (397,448,452–454,457,458,462, 472,473). The FSH response to GnRH also increases, and the response may be greater than that in the normal menstrual cycle (453,472,474–477). When ovarian feedback is minimal and GnRH/LH pulse frequency is very low in early lactation, FSH pulses coinciding with LH pulses may occur on rare occasions, but this association disappears as GnRH/LH pulse frequency increases (Fig. 13) (440).

Luteinizing Hormone In contrast to FSH, LH levels only increase to the lower limit of normal by 20 days postpartum and remain suppressed in the majority of women

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throughout most of the period of lactational amenorrhea (397,399,407,440,452–458,462,463,472,478–480) (Figs. 12 and 13). The LH response to GnRH is also diminished during early lactation (453,474–478) but from around 12 weeks onward the LH responses to GnRH given as single bolus injections, or as a series of hourly pulses are within the normal nonlactating menstrual cycle range (463,471,476). The low LH levels are associated with very low-amplitude pulses of LH at a frequency similar to, or less than, that of the luteal phase (443,444,478). These pulses may occur either infrequently with normal amplitude (Fig. 13) (386) or at regular intervals with low-amplitude (480) throughout the 24 hours. There is no evidence for enhanced pulsatile LH secretion during sleep (440,480) as observed during puberty (481). In some cases, and at different times during the period of amenorrhea, basal levels of LH increase to within the normal menstrual-cycle range; also, normal pulsatile secretion of LH, equivalent to that in the early follicular phase, is observed (Fig. 13) (440,464,478,480). This enhanced LH secretion is often accompanied by an increase in urinary estrogen excretion, indicative of

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FIG. 13. Pattern of resumption of pulsatile secretion of LH and FSH over a 24-hour period in fully breastfeeding women at (a) 4 weeks and (b) 8 weeks postpartum. Note that FSH and LH pulses only coincide at low LH (GnRH) pulse frequencies when negative feedback signals from the ovary are minimal. Pulsatile LH (GnRH) secretion resumes at a variable frequency and at random over 24 hours, with pulses also occurring at nighttime when prolactin response to suckling was maximal. All women remained amenorrheic for at least 20 weeks after sampling. [From (440).]

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2532 / CHAPTER 46 follicular development, but levels rarely increase to be equivalent to those in the normal follicular phase of the cycle. If breastfeeding continues at the same suckling frequency, LH secretion declines again, and a period of ovarian inactivity resumes (419,464,478). If suckling frequency is reduced or is only minimal, the increase in LH secretion may be maintained, with a consequent increase in estradiol secretion related to follicle development, and ovulation may occur (408,409,458,462,478). However, in fully breastfeeding women, in whom LH levels are suppressed, estradiol fails to induce a positive feedback response of either LH or FSH, and they are more sensitive to the negative feedback effects of estrogen (Fig. 12) (452,457,476,482,483) but not progesterone (455). This supports the concept that during breastfeeding in women any small increase in estradiol levels resulting from an increase in the pulsatile secretion of LH would be sufficient to switch off further secretion of LH, thus preventing normal follicular development (419,464,484). Treatment of non-breastfeeding women with the opioid antagonists naloxone (485) or naltrexone (479) did not affect LH between days 7 and 10 postpartum but transiently increased FSH and LH from day 15 onward, the response matching the increased response to GnRH (485) and the return of steroid secretion from the developing follicles. In breastfeeding women neither naloxone (476,477) nor naltrexone (479) affected LH or FSH.

Prolactin and Suckling The close association between the plasma levels of prolactin and the duration of infertility has led to the suggestion that prolactin per se may be involved in the suppression of gonadotropin secretion in women (397,399,400,430,431). Indeed, a reduced prolactin response to suckling, particularly at night, is correlated with an earlier resumption of ovulatory cycles in some (406,432,450) but not other (440) studies. The increase in estradiol secretion associated with follicular development prior to first menses postpartum is negatively correlated with the plasma level of prolactin in some but not all studies (396,397,400,431,439). However, the suckling-related increase in prolactin is not acutely related to any inhibition of basal or pulsatile secretion of LH (433,436,440,458,478). It is clear, however, that the level of prolactin postpartum in women is related to the amount of suckling during a 24-hour period (396–398,406,430–433,439,440). Thus, the relationship between prolactin and resumption of ovarian activity may be indirect: The decline in prolactin levels reflects a decrease in suckling

activity, while it is this decrease in suckling that allows the resumption of normal LH secretion (464). A difference in the sensitivity of the estradiol feedback system in terms of enhancing prolactin secretion and suppression of gonadotrophin secretion has been reported (486). Thus, women who had high prolactin levels associated with low estradiol levels at 38 weeks of pregnancy tended to have a prolonged duration of lactational amenorrhoea (486). Whether prolactin is involved directly is not clear, but an increase in sensitivity to estradiol in the prolactin secretion system could be mirrored by a similar increased sensitivity to estradiol in the gonadotropin axis, helping to maintain suppression of normal pulsatile GnRH secretion (454,476). A continuation of breast-feeding at night is associated with a longer duration of lactational amenorrhea (396,431), although night time feeding tends to occur more often in women who breastfeed frequently over a 24-hour period. Nevertheless, a continuation of night time breastfeeding has been associated with the continued occurrence of inadequate luteal function when ovulatory cycles have resumed in women who continue to breastfeed (461,467). The prolactin response to suckling appears to be greater in the afternoon than in the morning, when suckling is infrequent (437). However, pulsatile release of LH occurs throughout the 24-hour period (433,440,480), and the presence or absence of LH pulses is not related to the pattern of prolactin secretion, particularly at night, when prolactin levels and responses to suckling are maximal and LH pulses occur (440). Because the start of the preovulatory surge during the normal menstrual cycle occurs at night in the majority of women (487,488), it may be that nighttime suckling is more likely to suppress the generation of a normal preovulatory LH surge, thus leading to the formation of an inadequate CL (464). The possibility that high levels of prolactin might inhibit normal follicular development in women by a direct action at the ovary has been reviewed in detail previously (484,489). Although prolactin may (490) or may not (491,492) suppress estradiol secretion from human granulosa cells cultured in vitro, there is little evidence that a drug- or anesthetic-induced increase in prolactin around the preovulatory LH surge or during the luteal phase affects normal ovarian activity in any significant way (493). Indeed, an increase in prolactin secretion naturally occurs during the normal preovulatory surge of LH during the menstrual cycle (487). Drug-induced hyperprolactinemia during the follicular phase can block normal follicular development and ovulation (484); however, a direct effect of the drug on the release of LH, independent of its effect on prolactin, cannot be ruled out and has

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been reported (484). Thus, it is still not clear whether the elevated levels of prolactin during lactational amenorrhea in women play a significant role in the inhibition of LH release and ovarian activity. It is probable that, as in other species, prolactin plays only a minor role and that the principal effect is on direct suckling-induced inhibition of GnRH/LH release.

Influence of Nutritional Status There is no clear relationship between maternal nutritional status and the duration of lactational amenorrhea (494–502) perhaps related to the fact that perceived nutritional requirements for breastfeeding women may be overestimated (497) due to an increase in metabolic efficiency during lactation in women (498). Nevertheless, it is well recognized that women experience a period of hyperphagia during breastfeeding, which is probably directly related to the suckling stimulus. At present there is no evidence of alterations in leptin levels during lactation in breastfeeding women (503,504), although these studies need to be extended to more long-term breastfeeding. Low body fat, which may reduce fertility in breastfeeding women once menstruation has resumed (407), is associated with a marginal increase in prolactin (395,398,411,413,431), probably related to an increase in suckling activity (499,500). However, body mass index (BMI) per se does not appear to affect the duration of lactational infertility since ovulatory cycles resumed at the same time in women with very different BMIs, even though well-nourished women resumed regular cycles earlier (502). This suggests that the resumption of GnRH/LH pulsatile secretion sufficient to stimulate follicle steroid secretion may occur earlier in better nourished women, but that the positive feedback response to estradiol allowing generation of the preovulatory LH surge may be delayed. Thus, it appears that lactational amenorrhoea occurs for at least 10 months in well-nourished women when in positive energy balance suggesting that the suckling stimulus alone is sufficient to suppress gonadotrophin secretion and ovarian activity. Thereafter with longer duration of lactational amenorrhoea the indirect influence of negative energy balance may become of increasing importance adding to the effect of suckling (505). In general there is no strong evidence for a major effect of nutrition in the duration of lactational amenorrhoea, at least during the early stages of lactation (501,506,507); but emerging evidence that when the demands of continued breastfeeding results in a negative energy balance in the mother, then this can prolong the duration, as seen in other species (Fig. 1).

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MECHANISMS OF SUCKLING-INDUCED OVARIAN INACTIVITY Several common features of the effects of suckling on gonadotropin release have emerged in the species for which adequate data are available. It is clear that the suckling stimulus alone at least in early lactation in most species, is sufficient to maintain an inhibition on the GnRH pulse generator limiting pulsatile LH secretion regardless of nutritional status, a direct route of action (Fig. 1). However, as lactation advances and the young demand more milk to supply their nutrient requirements, the effects of nutritional status becomes more important, an indirect route of action (Fig. 1) (72), but when this happens in lactation appears to differ between species, and will obviously depend on the requirements of the offspring. In species with large litter sizes such as rats, or where domestic animals have been bred for maximum milk yield, a state of negative energy balance will emerge fairly quickly, even though lactation is associated with a large increase in food intake, hyperphagia. In other species such as primates with one or two offspring this nutritional deficit may not appear to be so extreme and the role of negative energy balance may remain minimal. What is emerging is that there may be common pathways that link the effects of the direct neural suckling stimulus on the one hand, and negative energy balance on the other, in the mechanisms whereby pulsatile GnRH secretion is inhibited during lactation (Fig. 14) (72,73), or where in some cases ovarian responsiveness may be compromised in extreme cases (283,285,286,344). Before examining these potential pathways, the common features of sucklinginduced suppression of gonadotropin secretion and consequent ovarian function will be summarized. In most species, both pituitary and plasma FSH return to normal estrous or menstrual-cycle levels soon after delivery, with normal responses to GnRH paralleling these changes. There is also a rapid increase in FSH after ovariectomy, although this response may be somewhat suppressed when the suckling intensity is high, e.g., in the pig (114) or during early lactation in the monkey at a time when pituitary levels of FSH are also reduced (381). The secretion of FSH requires minimal GnRH stimulation, and a slow pulse frequency or low amplitude pulses of GnRH are sufficient to activate FSH-β mRNA transcription with subsequent synthesis of FSH which is then released mainly through a constitutive pathway with little storage in the pituitary gonadotropes (508–510). Thus, the amount of FSH released is mainly controlled by the rate of synthesis which in turn is controlled mainly by the negative feedback effects of gonadal steroids, particularly

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?

Food intake hyperphagia

ARH PRLR =

+

Prolactin

Dopamine

_

LHA Leptin R Ghrelin R

Orexin

NPY PRLR

_ =

+

Leptin inhibition of NPY

+

GnRH neurone

Y5

NPY

Tyrosine Hydroxylase TIDA neurones

DMH

_

NPY

MCH

+ _

+

−/+

Orexin A

Specific to suckling

=

Leptin Leptin R

+ = Ghrelin

Direct route Negative energy balance

Brain stem

Suckling

Indirect route metabolic

Food intake hyperphagia

+ Prolactin

Milk production

Y1 Median eminence

LH and FSH pituitary

FIG. 14. Schematic diagram of the potential direct and indirect routes of the suckling stimulus within the hypothalamus that ultimately leads to the complete or partial suppression of pulsatile GnRH release resulting in inhibition of normal ovarian activity and the infertility associated with suckling. Note that the major final common pathway are the GnRH neurones with the principal immediate intermediate being neuropeptide Y (NPY) emanating from neurones in the arcuate nucleus (ARH) and signaling through Y-5 receptors in the cell body and Y-1 receptors at the terminals of GnRH neurones. These NPY neurones are directly stimulated by the suckling stimulus through the direct route, and by the indirect route through the effects of the negative energy balance induced by the metabolic load of producing milk. This latter route becomes more influential as lactation progresses, but if and when this additional effect of the indirect route occurs will depend on species (Fig. 1). Suckling also induces an increase in food intake (hyperphagia) though a direct effect on NPY-expressing neurons in the dorsomedial hypothalamus (DMH). The effects of negative energy balance through the indirect route are associated with changes orexin A expression in the lateral hypothalamic area (LHA) potentially directly affecting the GnRH neurons, and other factors such as increased ghrelin and decreased leptin which increase NPY expression through their respective receptors (Ghrelin R and Leptin R) in the ARH all resulting in hyperphagia. The increase in secretion of prolactin occurring through suckling-induced decreased dopamine release from tuberoinfundibular (TIDA) neurons in the ARH, appears to play an indirect role through maintenance of milk production. Most of these pathways have only been elucidated in the rat and will need to be confirmed in other species. The ultimate endpoint is a modulation of the GnRH pulse generator with suppression of normal pulsatile LH secretion and inhibition of ovarian function. Thick lines represent defined pathways elucidated in more than one species; thin lines indicate pathways clearly defined in the rat. The dotted line linking prolactin directly to the GnRH neurons indicates a potential, but unproven, pathway in vivo.

estradiol, and peptides, principally inhibin, through direct actions at the pituitary gland (419,508–510). The reasonably rapid return of apparently normal levels of FSH observed during lactation probably arises because suckling suppresses GnRH output but does not inhibit it completely, allowing a resumption of FSH-β mRNA transcription, and hence FSH synthesis and secretion. This may stimulate ovarian follicle development, but, because of the reduced GnRH

input, LH pulsatile drive to the follicles to stimulate steroid production, particularly estradiol, is reduced resulting in a reduced negative feedback signal on FSH secretion. Thus, the major limiting factor with regard to continued follicular development is not FSH (419). In contrast, in all species for which there are adequate data, suckling clearly inhibits the normal pulsatile release of LH and it is this absence of sufficient pulsatile LH secretion to drive the final stages

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of follicle development that limits ovarian activity. During early lactation in most species and throughout lactation when the suckling intensity is maintained, for example, by the multiple suckling of litters, LH pulses occur infrequently and the response to ovariectomy is suppressed. Since pulsatile LH release occurs in response to the pulsatile secretion of GnRH from the hypothalamus, releasing LH-containing granules from the gonadotropes [see (509)], the suckling stimulus appears to inhibit the normal pattern of hypothalamic release of GnRH with LH pulses occurring infrequently. As the suckling stimulus declines with advancing lactation (related to the growth of the young and their use of alternative food sources), the frequency of pulsatile release of LH increases. The failure of, or reduction in, positive feedback action of estradiol almost certainly relates to this decrease in the ability of the hypothalamus to increase GnRH output. Conversely, an enhanced negative feedback action of estradiol would be expected if the positive effect of GnRH was suppressed by the suckling stimulus. Only when suckling has declined to the point where GnRH release is no longer inhibited does normal pulsatile LH release occur, resulting in normal follicular development. Even then, inadequate CL may be formed, perhaps because of a reduction in the release of LH during and after the pre-ovulatory LH surge as a result of the continued suckling stimulus reducing the surge release of GnRH. The close correlation between suckling and prolactin had led to the suggestion that the elevated levels of prolactin may be directly involved with the suppression of hypothalamic GnRH release but there is little evidence that prolactin has any major action directly on the ovary to reduce ovarian activity. Lactation demands the maintenance through the suckling stimulus of high levels of prolactin and this is achieved through a reduction in the negative feedback effect of prolactin which normally operates through the stimulation of dopamine release from tuberoinfundibular (TIDA) neurones in the arcuate nucleus (ARH) to directly inhibit prolactin release from the lactotropes. During lactation these TIDA neurones become less responsive to prolactin resulting in reduced release of dopamine, related to a reduction in tyrosine hydroxylase associated with a reduction in the expression of the long form of the prolactin receptor in these TIDA neurones (511–516). Opioid neurones acting through µ and κ, but not δ receptors are directly involved in this suckling-regulated decreased dopamine production by the TIDA neurones and explains why specific, or broad spectrum opioid receptor blockers or immunoneutralization of opioids suppress prolactin secretion during lactation in most species. These mechanisms that maintain prolactin secretion in lactation operate mostly through the TIDA

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neurons, and at present no link has been established between these TIDA neurones and the GnRH neuronal system (Fig. 14) (73). Prolactin receptors are present on the dorsomedial (DMH) neurones in the hypothalamus and prolactin increases the direct action of suckling on stimulating neuropeptide Y (NPY) expression in these DMH neurones (Fig. 14) (517–519) which is related to increases in food intake [see (73)]. Again, there is no known link between DMH and GnRH neurones. Suckling also increases prolactin receptor expression in the ventrolateral and ventromedial preoptic (VLPO and VMPO, respectively) nuclei (520); and while there is no co-localization of prolactin receptors with any neurones, the VLPO contains a large number of GnRH neurones (521) and the VMPO has been implicated in the regulation of the preovulatory LH surge in the rat (522). Furthermore, while suckling increased GABA turnover in the VLPO in regions unconnected with GnRH neurons, an increase in GABA turnover has been linked with the reduction in the responsiveness of GnRH neurones to excitatory amino acid stimulation (523). Thus, while the sites at which, and mechanisms through which, prolactin may act in the hypothalamus are emerging, there is still no clear direct link between prolactin per se and suppression of the GnRH pulse generator. A clearer picture is emerging in the link between suckling and the pathways involved in maintaining food intake (73) which appears to provide a common pathway for both the direct suckling stimulus, and the indirect nutritional energy balance input (Fig. 14). A major factor in regulating food intake is NPY particularly that expressed in the ARH neurones. Increases in NPY are associated with increased food intake, hyperphagia, a situation which occurs as a consequence of the suckling stimulus through a direct route (Fig. 14) (73). Within non-TIDA neurones in the ARH nucleus NPY expression is greatly increased in neurones that form direct links to the GnRH neurones either through Y5 receptors expressed on the GnRH neuronal cell bodies, or Y1 receptors on GnRH neurone fibers and terminals at the median eminence (517–519). This increase in NPY occurs independently of prolactin (517). Leptin, the feedback protein released from fat stores simulates LH secretion in the nonlactating animal and leptin receptors are present on NPY neurones in the ARH (524). During the stages of negative energy balance in lactation both leptin levels (524) and its receptors in the ARH (525) decrease. This would effectively reduce the positive effects of leptin on suppressing NPY expression in the ARH providing another route to suppression of GnRH neuronal activity (Fig. 14). Ghrelin, a GH releasing peptide produced in the stomach and gastrointestinal tract (526) is elevated in plasma in situations of

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2536 / CHAPTER 46 energy deficit and stimulates food intake and reduces pulsatile LH secretion when given (527–529). Ghrelin receptors co-localize with NPY mRNA-expressing neurones in the ARH, again providing a link between negative energy balance and NPY (530). Finally NPY can increase the activity of orexin neurones in the lateral hypothalamic area which make direct contacts through orexin-1, orexin A-specific receptors, with GnRH neurones (531), and orexin inhibits LH secretion when steroid levels are low (528), as in early lactation at least (Fig. 14). From all these observations a specific role for elevated NPY expression in neurones in the ARH in suppressing the GnRH pulse generator emerges. This increase in ARH NPY can be stimulated both through the direct effects of suckling alone, or through the indirect effects of reduced energy balance on the secretion of factors known to be altered in this state. The role of the suckling-induced increase in prolactin would appear to be mainly, if not exclusively, in the production of milk that leads to alterations in energy balance, enhancing the suppressive effects of the suckling stimulus in suppressing the GnRH pulse generator. The importance of the energy balance effects will depend on species, but would be without major effects, unless very extreme, in the absence of suckling. In most species where there is adequate data, there is no doubt that the strength of the suckling stimulus, be it the intensity of sucking within sucking bouts, the frequency or duration of suckling, or the inter-suckling interval, is the principal determinant of the duration of the suckling-induced delay in resumption of ovarian activity at least in early lactation. As lactation progresses the effects of suckling are amplified if a condition of negative energy balance related to continued milk production ensues. At what point, if ever, this transition from direct effects of suckling alone, to added indirect effects of negative energy balance occurs will depend on the metabolic load, and the ability to respond to this in individual mothers. It does now appear that a common pathway linking the direct suckling and indirect energy balance pathways has emerged in the potential role of NPY (Fig. 14). The final common pathway remains the regulation of pulsatile secretion of GnRH which ultimately controls pituitary gonadotropin secretion and hence ovarian function. REFERENCES 1. Everett, J. W. (1961). The mammalian female reproductive cycle and its controlling mechanisms. In Sex and Internal Secretions (W. C. Young, Ed.), Vol. 1, pp. 497–555. Williams & Wilkins, Baltimore. 2. Connor, J. R., and Davis, H. N. (1980). Postpartum estrus in Norway rats: 1. Behaviour. Biol. Reprod. 23, 994–999.

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43. Li, C., Chen, P., and Smith, M. S. (1998). The acute suckling induces the expression of neuropeptide Y (NPY) in cells in the dorsomedial hypothalamus and increases NPY expression in the arcuate nucleus. Endocrinology 139, 1645–1652. 44. Gallo, R. V. (1981). Pulsatile LH release during periods of low levels LH secretion in the rat estrous cycle. Biol. Reprod. 24, 771–776. 45. Higuchi, T., and Kawakami, M. (1982). Changes in the characteristics of pulsatile luteinizing hormone secretion during the oestrous cycle and after ovariectomy and oestrogen treatment in female rats. J. Endocrinol. 94, l77–182. 46. Smith, M. S., and Lee, L. R. (1989). Modulation of pituitary gonadotropin-releasing hormone receptors during lactation in the rat. Endocrinology 124, 1455–1461. 47. Lee, L. R., Haisenleder, D. J., Marshall, J. C., and Smith, M. S. (1989). Expression of alpha-subunit and luteinizing hormone (LH) beta messenger ribonucleic acid in the rat during lactation and after pup removal: relationship to pituitary gonadotropinreleasing hormone receptors and pulsatile LH secretion. Endocrinology 124, 775–782. 48. Lee, L. R., Haisenleder, D. J., Marshall, J. C., and Smith, M. S. (1989). Effects of progesterone on pulsatile luteinizing hormone (LH) secretion and LH subunit messenger ribonucleic acid during lactation in the rat. Endocrinology 124, 2128–2134. 49. Steger, R. W., and Peluso, J. J. (1978). Gonadotrophin regulation in the lactating rat. Acta Endocrinol. 88, 668–675. 50. Smith, M. S. (1984). Effects of the intensity of the suckling stimulus and ovarian steroids on pituitary gonadotropinreleasing hormone receptors during lactation. Biol. Reprod. 31, 548–555. 51. Minaguchi, H., and Meites, J. (1967). Effect of suckling on hypothalamic LH releasing factor and prolactin inhibiting factor, and on pituitary LH and prolactin. Endocrinology 80, 603–607. 52. Smith, M. S., and Rheinhart, J. (1993). Changes in gonadotropin-releasing hormone receptor mRNA content during lactation and after pup removal. Endocrinology 133, 2080–2084. 53. Clayton, R. N., Solano, A. R., Garcia-Vila, A., Dufau, M. L., and Catt, K. J. (1980). Regulation of pituitary receptors for gonadotropin-releasing hormone during the rat estrous cycle. Endocrinology 107, 699–705. 54. Marks, D. L., Smith, M. S., Clifton, D. K., and Steiner, R. A. (1993). Regulation of GnRH and galanin gene expression in GnRH neurons during lactation in the rat. Endocrinology 133, 1450–1455. 55. PohI, C. R., Lee, L. R., and Smith, M. S. (1989). Qualitative changes in luteinizing hormone and prolactin responses to N-methyl-aspartic acid during lactation in the rat. Endocrinology 124, 1905–1911. 56. Abbud, R., Hoffman, G. E., and Smith, M. S. (1992). Lactation inhibits hippocampal and cortical expression of cFos in response to NMDA but not to kainite receptor agonists. Mol. Cell. Neurosci. 3, 244–250. 57. Abbud, R., Hoffman, G. E., and Smith, M. S. (1993). Cortical refractoriness to N-methyl-D, L-aspartic acid (NMA) stimulation in the lactating rat: recovery after pup removal and blockade of progesterone receptors. Brain Res. 604, 15–23. 58. Hodson, C. A., Simpkins, J. W., and Meites, J. (1978). Inhibition of luteinizing hormone release and luteinizing hormone releasing hormone action by the ovaries of postpartum lactating rats. Endocrinology 102, 832–836. 59. Lee, L. R., Paul, S. J., and Smith, M. S. (1989). Dose response effects of pulsatile GnRH administration on restoration of pituitary GnRH receptors and pulsatile LH secretion during lactation. Neuroendocrinology 49, 664–668.

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