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Changing diurnal and pulsatile rhythms during aging
Neurobiologyof Aging,Vol. 15, No. 4, pp. 503-507, 1994 Copyright© 1994ElsevierScienceLtd Printedin the USA. All fightsreserved 0197-4580/94$6.00 + .00
Pergamon 0197-4580(94)E0048-5
Changing Diurnal and Pulsatile Rhythms During Aging PHYLLIS M. WISE, NANCY G. WEILAND, KATHRYN SCARBROUGH AND JONATHAN M. LLOYD
Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201 Female reproductive function depends on intricately coordinated cyclic, circadian, and ultradian neuroendocrine and endocrine rhythms. These rhythms synchronize the reproductive events that permit the organism to be fertile at optimal times (for reviews see 22,31). Although the interval between each preovulatory surge of luteinizing hormone (LH) varies widely among species, this interval is remarkably consistent and predictable in sexually mature females within a strain of animals when environmental cues are maintained. Diurnal oscillators influence the ability of animals to exhibit normal reproductive cycles. The importance of a circadian neural pacemaker was first recognized from studies performed with laboratory rodents. Everett and Sawyer and their colleagues (11,12, 40) proposed that diurnal neural cues that occur during a "critical period" each day govern the timing and regularity of preovulatory gonadotropin surges. Studies in other experimental animals and in humans (42,44) also establish that ovulation and cyclic LH surges occur predominantly at predictable times even when the light:dark cycle is not well controlled. Studies, using a variety of methods, clearly establish that the maintenance of diurnal rhythmicity depends on neural pacemaker(s) or "biological clocks". The major biological clock, or circadian oscillator, resides in the suprachiasmatic nucleus of the hypothalamus. This brain region is essential for the regular incidence of cyclic gonadotropin release resulting in ovulation (5,15,24) as well as the circadian rhythmicity of other physiological functions (7,20,43). Specific rhythms and synchrony of neurochemical events within this neural pacemaker and other areas of the brain determine the timing of preovulatory gonadotropin surges and ensuing ovulation (8,21,45). In addition to the diurnal pattern of neurotransmitter and hormone release, animals exhibit ultradian oscillations (6,9,29). This ultradian rhythm varies during the day and during the reproductive cycle and may contribute to normal reproductive cyclicity (1,13, 14,38,39). The occurrence of regularly timed pulses of gonadotropin hormone-releasing hormone (GnRH) is thought to be regulated by the hypothalamicpulse generator (31,38). Considerable evidence suggests that the pulse generator resides in the medial basal hypothalamus because surgical isolation of this brain region from neurochemical input from other areas does not disrupt the pulsatility of GnRH release (2,26). Neuroendocrine mechanisms in the preoptic/anterior hypothalamic area may also contribute to GnRH pulsatility (19). Our laboratory has been interested in the role that changing cyclic, diurnal, or pulsatile patterns of neuroendocrine and endocrine events play in the middle-age transition to infertility. We reasoned that if ovulation depends on the cyclic release of hormones, which, in turn, depends on a complex constellation of diurnal and ultradian neuroendocrine and endocrine events that
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FIG. 1. Alpha-l-adrenergicreceptor densities in the medial preoptic nucleus of young, middle-aged,and old ovariectomizedrats. Receptor concentrations in young rats exhibit a diurnalrhythm. In middle-agedrats, no rhythm is detectable; however mean densitiesare not differentfrom those in youngrats. In old animals,the rhythm is absent and the average density of receptors is lower (47). 503
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WISE ET AL.
must occur at specific times in specific sequences, then subtle changes in the ultradian or diurnal rhythm of one or more of these factors may compromise the regularity of reproductive cycles.
is no longer detectable and changes in the average density of receptors is evident by the time animals are old. AGE-RELATED CHANGES IN THE ULTRADIAN RHYTHMS OF HORMONE SECRETION
AGE-RELATED CHANGES IN THE DIURNAL RHYTHM OF NEUROENDOCRINEACTIVITY
In female rats, as in human females, reproductive function declines during middle age. Female Sprague-Dawley rats become sexually mature between 1 and 2 months of age and exhibit regular 4- to 5-day estrous cycles. During middle age, at approximately 7-9 months of age, an increasing percent exhibit irregular cycles of 6--10 days in length. Finally, when rats are between 12 and 18 months of age, the majority become acyclic and exhibit constant vaginal estrus or persistent diestrus (17,18,33). We have previously reported that (a) norepinephrine is an important neuromodulator for release of GnRH (37); (b) a unique diurnal pattern of turnover rates exists in specific hypothalamic nuclei that are thought to regulate the cyclic release of LH on proestrus (37) and during steroid-induced LH surges (36,37,53); (c) middle-aged rats no longer exhibit this pattern of norepinephrine turnover in key regions of the hypothalamus (48,50). Most evidence supports the concept that norepinephrine's stimulatory effect on GnRH release is mediated by al-adrenergic receptors (10,16,23). Therefore, we have examined whether changes in the diurnal pattern of norepinephrine turnover are accompanied by changes in the density of cq-adrenergic receptors. We measured the density of a l receptors at multiple times of day in rats of different ages to determine (a) whether receptor densities exhibit a diurnal rhythm and (b) whether changes in receptor densities or the diurnal rhythm of their densities change during the middle-age period (47). Such changes could contribute to changes in the ability of aging animals to respond to adrenergic stimulation. Using autoradiographic methods, we found that the density of these receptors exhibit a diurnal rhythm in both the medial preoptic nucleus (see Fig. 1) and suprachiasmatic nucleus of young rats. Both of these brain regions are pacemaker areas and are involved in the maintenance of biological rhythms (5,7,35,43). In middle-aged rats, the diurnal rhythm in receptor density in these brain regions
GnRH secretion is pulsatile (6,29,30). The amplitude and frequency of GnRH pulses determines, in part, the amplitude and frequency of LH pulses (25,28). We reasoned that if changes in hypothalamic function occur during the initial stages of reproductive aging, we may be able to detect changes in the pulsatility of LH release. To assess whether chronological age and reproductive status of the animals interact to result in changes in GnRH release we used 4 experimental groups: young regularly cycling (2-3 months) and three groups of middle-aged (10-12 months) rats that were in various stages of reproductive senescence (41). The first group of middle-aged rats were regular cyclers at the time of ovariectomy, the second group of middle-aged rats were cycling irregularly at the time of ovariectomy, and the third middle-aged group had exhibited at least 14 consecutive days of cornified smears before they were ovariectomized. Rats exhibiting these stages of reproductive aging are known to have been exposed to different patterns of estradiol secretion. Because many investigators (3,4,27,32,34) have shown clearly that exposure to endogenously secreted or exogenously administered estrogen can modulate the rate of reproductive aging, dividing the middle-aged groups of rats into subgroups depending on reproductive status allowed us to evaluate the contribution of chronological versus reproductive age to changes in pulsatility. Various parameters of pulsatility change with chronological age and reproductive status: (a) amplitude decreased in all groups of middle-aged rats regardless of previous estrous cycle history; (b) changes in the responsiveness of the pituitary gland to GnRH stimulation are evident in middle-aged rats regardless of previous reproductive status; (c) pulse frequency, a more accurate indicator of hypothalamic function, decreased by the time middle-aged rats showed irregular estrous cycles but was not different from young rats if cycles were still regular at the time of ovariectomy (41). Further analysis of the frequency distribution of interpeak intervals in the four experimen-
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and ultradian oscillation are altered with age and may contribute to reproductive senescence (for reviews see 46,49,51). It is interesting to speculate that deterioration in a central element that influences these rhythms may occur during aging and may account for the seemingly unrelated changes that occur in rhythmic neural functions. The critical role of the suprachiasmatic nucleus, often considered the master oscillator or biological clock is well recognized. We hypothesized that if the timing of several neural events in the suprachiasmatic nucleus were altered with age, middle-aged rats would show a change in the circadian rhythm of local cerebral glucose utilization (LCGU), because this experimental endpoint reflects overall neural activity. In turn, age-related alterations in the rhythmicity of overall neural function may reflect a fundamental change in the circadian activity of the biological clock. We measured glucose utilization in this region of the brain using the 2-deoxy-D-1-14C glucose method with modifications that allowed us to assess glucose utilization in unrestrained rats (54). We found that in young rats, LCGU is elevated during the light period compared to the dark (Fig. 3). A unique aspect of the glucose rhythm in young rats is the secondary increase between 1000 hours and 1200 hours. This increase precedes the onset of the estradiolinduced LH surge and coincides with the increase in norepinephrine turnover. In middle-aged rats, although a circadian rhythm in glucose utilization is detectable, several notable differences exist. Glucose utilization rises more slowly after the lights go on and decreases prematurely during the afternoon prior to lights off. In addition, there is no secondary change during the morning; therefore glucose utilization is uniform during the entire light period and there is no increase preceding the time of the expected LH surge. The data suggest that aging involves a loss in the precision and/or synchrony of the timing of the diurnal rhythms or the activities of multiple neurotransmitters during middle age, thereby disrupting cyclic reproductive function. In summary, evidence supports the conclusions that (a) changes in hypothalamic function occur during the initial stages of reproductive aging and (b) subtle alterations that reflect changes in the integrity of the biological clock and the hypothalamic pulse generator or their ability to entrain rhythmic activity of multiple neurotransmitters occur during middle age and may be important elements in the cascade of events that leads to acyclicity and infertility in aged animals.
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animals that showed no deterioration in the regularity of their estrous cycles prior to ovariectomy. The data strongly suggest that changes in the hypothalamic pulse generator occur early during the transition to acyclicity and may play a key causative role in this age-related transition.
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FIG. 3. Local cerebral glucose utilization in the ventral (SCN-V) and dorsal (SCN-D) aspects of the suprachiasmatic nucleus in young (&) and middle-aged (0) ovariectomized estradiol-treated rats. In young rats, LCGU increased when lights went on between 0300 and 0500h, and again just before the initiation of the LH surge between 1000 and 1200h. They decreased when lights went off between 1700 and 1900h. In middle-aged rats, LCGU increased between 0300 and 1000h and decreased between 1400 and 1900h (52).
tal groups revealed that the distributions of the interpeak intervals differ significantly in middle-aged rats before they show any change in estrous cyclicity. The dominant period exhibited by these middle-aged rats is the same as we observed in young rats; however, a smaller frequency of shorter interpeak intervals and a greater frequency of the longer periods between pulses occur when compared to young (Fig. 2). This shift toward longer interpeak intervals becomes more pronounced in middle-aged animals that
ACKNOWLEDGEMENTS This research was supported by NIH Grants AG-02224, AG-05357, HD-15955, and HD-07170. PMW is an NIH MERIT Awardee.
REFERENCES
1. Baird, D. T. Pulsatile secretion of LH and ovarian estradiol during the follicular phase of the sheep estrous cycle. Biol. Reprod. 18:359-364; 1978. 2. Blake, C. A.; Sawyer, C. H. Effects of hypothalamic deafferentation on the pulsatile rhythm in plasma concentrations of luteinizing hormone in ovariectomized rats. Endocrinol. 94:730-736; 1974.
3. Brawer, J. R.; Naftolin, F.; Martin, J.; Sonnenschein, C. Effects of a single injection of estradiol valerate on the hypothalamic arcuate nucleus and on reproductive function in the female rat. Endocfinol. 103:501-512; 1978. 4. Brawer, J. R.; Ruf, K. B.; Naftolin, F. The effects of estradiolinduced lesions of the arcuate nucleus on gonadotropin release in
506
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17. 18. 19.
20. 21.
22.
23.
24.
25.
26.
response to preoptic stimulation in the rat. Neuroendocrinol. 30:144149; 1980. Brown-Grant, K.; Raisman, G. Abnormalities in reproductive function associated with the destruction of the suprachiasmatic nuclei in female rats. Proc. R. Soc. Lond. B. 198:279-296; 1977. Cannel, P. W.; Araki, S.; Ferin, M. Pituitary stalk portal blood collection in rhesus monkeys: evidence for pulsatile release of gonadotropin-releasing hormone (GnRH). Endocrinol. 99:243-248; 1976. Coen, C. W.; MacKinnon, P. C. B. Lesions of the suprachiasmatic nuclei and the serotonin-dependent phasic release of luteinizing hormone in the rat: Effects on drinking rhythmicity and on the consequences of preoptic area stimulation. J. Endocr. 84:231-236; 1980. Coombs, M. C.; Coen, C. W. Adrenaline turnover rates in the medial preoptic area and mediobasal hypothalamus in relation to the release of luteinizing hormone in female rats. Neurosci. 10:207-210; 1983. Dierschke, D. J.; Bhattacharya, A. N.; Atkinson, L. E.; Knobil, E. Circhoral oscillations of plasma LH levels in the ovariectomized rhesus monkey. Endocrinol. 87:850--853; 1970. Drouva, S. V.; Laplante, E.; Kordon, C. alphal-Adrenergic receptor involvement in the LH surge in ovariectomized estrogen-primed rats. Eur. J. Pharmacol. 81:341-344; 1982. Everett, J. W.; Sawyer, C. H. A 24-hour periodicity in the "LHrelease apparatus" of female rats, disclosed by barbiturate sedation. Endocrinol. 47:198-218; 1950. Everett, J. W.; Sawyer, C. H.; Markee, J. E. A neurogenic timing factor in control of the ovulatory discharge of luteinizing hormone in the cyclic rat. Endocrinol. 44:234-250; 1949. Filicori, M.; Santoro, N.; Merriam, G. R.; Crowley, W. F., Jr. Characterization of the physiological pattern of episodic gonadotropin secretion throughout the human menstrual cycle. J. Clin. Endocrinol. Metab. 62:1136-1144; 1986. Fox, S. R.; Smith, M. S. Changes in the pulsatile pattern of luteinizing hormone secretion during the rat estrous cycle. Endocrinol. 116: 1485-1492; 1985. Gray, G. D.; Sodersten, P.; Tallentire, D.; Davidson, J. M. Effects of lesions in various structures of the suprachiasmatic-preoptic region on LH regulation and sexual behavior in female rats. Neuroendocrinol. 25:174-191; 1978. Heaulme, M.; Dray, F. Noradrenaline and prostaglandin E2 stimulate LH-RH release from rat median eminence through distinct l-alphaadrenergic and PGE 2 receptors. Neuroendocrinol. 39:403-407; 1984. Huang, H. H.; Meites, J. Reproductive capacity of aging female rats. Neuroendocrinol. 17:289-295; 1975. Ingram, D. L. The vaginal smear of senile laboratory rats. J. Endocr. 19:182-188; 1959. Jarry, H.; Leonhardt, S.; Wuttke, W. A norepinephrine dependent mechanism in the preoptic/anterior hypothalamic area is involved in regulation of the GnRH pulse generator in ovariectomized rats. Neuroendocrinol. 1989. Kafka, M. S.; Marangos, P. J.; Moore, R. Y. Suprachiasmatic nucleus ablation abolishes circadian rhythms in rat brain neurotransmitter receptors. Brain Res. 327:344-347; 1985. Kalra, S. P. Catecholamine involvement in preovulatory LH release: reassessment of the role of epinephrine. Neuroendocrinol. 40:139144; 1985. Karsch, F. J. Central actions of ovarian steroids in the feedback regulation of pulsatile secretion of luteinizing hormone. Ann. Rev. Physiol. 49:365-382; 1987. Kaufman, J.-M.; Kesner, J. S.; Wilson, R. C.; Knobil, E. Electrophysiological manifestation of luteinizing hormone-releasing hormone pulse generator activity in the rhesus monkey: influence of alphaadrenergic and dopaminergic blocking agents. Endocrinol. 116:13271333; 1985. Kawakami, M.; Arita, J.; Yoshioka, E. Loss of estrogen-induced daily surges of prolactin and gonadotropins by suprachiasmatic nucleus lesions in ovariectomized rats. Endocrinol. 106:1087-1092; 1980. Kesner, J. S.; Wilson, R. C.; Kaufman, J.-M.; Hotchkiss, J.; Chen, Y.; Yamamoto, H.; Pardo, R. R.; Knobil, E. Unexpected responses of the hypothalamic gonadotropin-releasing hormone "pulse generator" to physiological estradiol inputs in the absence of the ovary. Proc. Natl. Acad. Sci. USA 84:8745-8749; 1987. Krey, L. C.; Butler, W. R.; Knobil, E. Surgical disconnection of the
W I S E ET AL.
27.
28.
29.
30. 31.
32.
33. 34.
35.
36.
37.
38.
39.
40. 41.
42. 43.
44. 45. 46. 47.
medial basal hypothalamus and pituitary function in the rhesus monkey. I. Gonadotropin secretion. Endocrinol. 96:1073-1087; 1975 (Abstract). Lapolt, P. S.; Matt, D. W.; Judd, H. L.; Lu, J. K. H. The relation of ovarian steroid levels in young female rats to subsequent estrous cyclicity and reproductive function during aging. Biol. Reprod. 35: 1131-1139; 1986. Levine, J. E.; Duffy, M. T. Simultaneous measurement of luteinizing hormone (LH)-releasing hormone, LH, and follicle-stimulating hormone release in intact and short-term castrate rats. Endocrinol. 122: 2211-2221; 1988. Levine, J. E.; Norman, R. L.; Gliessman, P. M.; Oyama, T. T.; Bangsberg, D. R.; Spies, H. G. In vivo gonadotropin-releasing hormone release and serum luteinizing hormone measurements in ovariectomized, estrogen-treated rhesus macaques. Endocrinol. 117:711721; 1985. Levine, J. E.; Powell, K. D. Microdialysis for measurement of neuroendocrine peptides. Meth. Enzymol. 168:166-181; 1989. Lincoln, D. W.; Fraser, H. M.; Lincoln, G. A.; Martin, G. B.; McNeilly, A. S. Hypothalamic pulse generators. Rec. Prog. Hormone Res. 41:369-419; 1985. Lu, J. K. H.; Lapolt, P. S.; Nass, T. E.; Matt, D. W.; Judd, H. L. Relation of circulating estradiol and progesterone to gonadotropin secretion and estrous cyclicity in aging female rats. Endocrinol. 116: 1953-1959; 1985. Mandl, A. M. Cyclic changes in the vaginal smears of senile nulliparous and multiparous rats. J. Endocr. 22:257-268; 1961. Naftolin, F.; MacLusky, N. J.; Leranth, C. Z.; Sakamoto, H. S.; Garcia-Segura, L. M. The cellular effects of estrogens on neuroendocrine tissues. J. Steroid Biochem. 29:215-228; 1988. Raisman, G.; Brown-Grant, K. The 'suprachiasmatic syndrome': endocrine and behavioural abnormalities following lesions of the suprachiasmatic nuclei in the female rat. Proc. R. Soc. Lond. B. 198:297314; 1977. Rance, N.; Wise, P. M.; Barraclough, C. A. Negative feedback effects of progesterone correlated with changes in hypothalamic norepinephrine and dopamine turnover rates, median eminence luteinizing hormone-releasing hormone, and peripheral plasma gonadotropins. Endocrinol. 108:2194-2199; 1981. Rance, N.; Wise, P. M.; Selmanoff, M. K.; Barraclough, C. A. Catecholamine turnover rates in discrete hypothalamic areas and associated changes in median eminence luteinizing hormone-releasing hormone and serum gonadotropins on proestrus and diestrous day 1. Endocrinol. 108:1795-1802; 1981. Rasmussen, D. D. Physiological interactions of the basic rest-activity cycle of the brain: pulsatile luteinizing hormone secretion as a model. Psychoneuroendocrinol. 11:389--405; 1986. Santoro, N.; Butler, J. P.; Filicori, M.; Crowley, W. F., Jr. Alterations of the hypothalamic GnRH interpulse interval sequence over the normal menstrual cycle. Am. J. Physiol. 255:E696-E701; 1988. Sawyer, C. H.; Everett, J. W.; Markee, J. E. A neural factor in the mechanism by which estrogen induces the release of luteinizing hormone in the rat. Endocrinol. 44:218-233; 1949. Scarbrough, K.; Wise, P. M. Age-related changes in the pulsatile pattern of LH release precede the transition to estrous acyclicity and depend upon estrous cycle history. Endocrinol. 126:884-890; 1990. Seibel, M. M.; Shine, W.; Smith, D. M.; Taymor, M. L. Biological rhythm of the luteinizing hormone surge in women. Fertil. Steril. 37:709-711; 1982. Szafarczyk, A.; Ixart, G.; Malaval, F.; Nouguier-Soule, J.; Assenmacher, I. Effects of lesions of the suprachiasmatic nuclei and of p-chlorophenylalanine on the circadian rhythms of adrenocorticotrophic hormone and corticosterone in the plasma, and on locomotor activity of rats. J. Endocr. 83:1-16; 1979. Testart, J.; Frydman, R.; Roger, M. Seasonal influence of diurnal rhythms in the onset of the plasma luteinizing hormone surge in women. J. Clin. Endocrinol. Metab. 55:374-377; 1982. Walker, R. F. Reinstatement of LH surges by serotonin neuroleptics in aging, constant estrous rats. Neurobiol. Aging 3:253-257; 1982. Walker, R. F. Impact of age-related changes in serotonin and norepinephrine metabolism on reproductive function in female rats: an analytical review. Neurobiol. Aging 5:121-139; 1984. Wetland, N. G.; Wise, P. M. Aging progressively alters the diurnal
DIURNAL AND PULSATILE RHYTHMS
48. 49, 50.
51.
rhythms and decreases the densities of alpha- 1-adrenergic receptors in selected hypothalamic regions. Endocrinol. 126:2392-2397; 1990. Wise, P. M. Norepinephrine and dopamine activity in microdissected brain areas of the middle-aged and young rat on proestrus. Biol. Reprod. 27:562-574; 1982. Wise, P. M. Aging of the female reproductive system. Rev. Biol. Res. Aging 1:195-222; 1983. Wise, P. M. Estradiol-induced daily luteinizing hormone and prolactin surges in young and middle-aged rats: Correlations with agerelated changes in pituitary responsiveness and catecholamine turnover rates in microdissected brain areas. Endocrinol. 115:801-809; 1984. Wise, P. M. Aging of the female reproductive system: A neuroendo-
507
crine perspective. In: E. E. Muller and R. M. MacLeod, eds. Neuroendocrine perspectives, Vol. 7. New York: Springer-Verlag; 1989: 117-168. 52. Wise, P. M.; Cohen, I. R.; Weiland, N. G.; London, E. D. Aging alters the circadian rhythm of glucose utilization in the suprachiasmatic nucleus. Proc. Natl. Acad. Sci. USA 85:5305-5309; 1988. 53. Wise, P. M.; Rance, N.; Barraclough, C. A. Effects of estradiol and progesterone on catecholamine turnover rates in discrete hypothalamic regions in ovariectomized rats. Endocrinol. 108:2186--2193; 1981. 54. Wise, P. M.; Walovitch, R. C.; Cohen, I. R.; Weiland, N. G.; London, E. D. Diurnal rhythmicity and hypothalamic deficits in glucose utilization in aged ovariectomized rats. J. Neurosci. 7:3469-3473; 1987.
Pergamon 0197-4580(94)E0048-5
Changing Diurnal and Pulsatile Rhythms During Aging PHYLLIS M. WISE, NANCY G. WEILAND, KATHRYN SCARBROUGH AND JONATHAN M. LLOYD
Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201 Female reproductive function depends on intricately coordinated cyclic, circadian, and ultradian neuroendocrine and endocrine rhythms. These rhythms synchronize the reproductive events that permit the organism to be fertile at optimal times (for reviews see 22,31). Although the interval between each preovulatory surge of luteinizing hormone (LH) varies widely among species, this interval is remarkably consistent and predictable in sexually mature females within a strain of animals when environmental cues are maintained. Diurnal oscillators influence the ability of animals to exhibit normal reproductive cycles. The importance of a circadian neural pacemaker was first recognized from studies performed with laboratory rodents. Everett and Sawyer and their colleagues (11,12, 40) proposed that diurnal neural cues that occur during a "critical period" each day govern the timing and regularity of preovulatory gonadotropin surges. Studies in other experimental animals and in humans (42,44) also establish that ovulation and cyclic LH surges occur predominantly at predictable times even when the light:dark cycle is not well controlled. Studies, using a variety of methods, clearly establish that the maintenance of diurnal rhythmicity depends on neural pacemaker(s) or "biological clocks". The major biological clock, or circadian oscillator, resides in the suprachiasmatic nucleus of the hypothalamus. This brain region is essential for the regular incidence of cyclic gonadotropin release resulting in ovulation (5,15,24) as well as the circadian rhythmicity of other physiological functions (7,20,43). Specific rhythms and synchrony of neurochemical events within this neural pacemaker and other areas of the brain determine the timing of preovulatory gonadotropin surges and ensuing ovulation (8,21,45). In addition to the diurnal pattern of neurotransmitter and hormone release, animals exhibit ultradian oscillations (6,9,29). This ultradian rhythm varies during the day and during the reproductive cycle and may contribute to normal reproductive cyclicity (1,13, 14,38,39). The occurrence of regularly timed pulses of gonadotropin hormone-releasing hormone (GnRH) is thought to be regulated by the hypothalamicpulse generator (31,38). Considerable evidence suggests that the pulse generator resides in the medial basal hypothalamus because surgical isolation of this brain region from neurochemical input from other areas does not disrupt the pulsatility of GnRH release (2,26). Neuroendocrine mechanisms in the preoptic/anterior hypothalamic area may also contribute to GnRH pulsatility (19). Our laboratory has been interested in the role that changing cyclic, diurnal, or pulsatile patterns of neuroendocrine and endocrine events play in the middle-age transition to infertility. We reasoned that if ovulation depends on the cyclic release of hormones, which, in turn, depends on a complex constellation of diurnal and ultradian neuroendocrine and endocrine events that
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FIG. 1. Alpha-l-adrenergicreceptor densities in the medial preoptic nucleus of young, middle-aged,and old ovariectomizedrats. Receptor concentrations in young rats exhibit a diurnalrhythm. In middle-agedrats, no rhythm is detectable; however mean densitiesare not differentfrom those in youngrats. In old animals,the rhythm is absent and the average density of receptors is lower (47). 503
504
WISE ET AL.
must occur at specific times in specific sequences, then subtle changes in the ultradian or diurnal rhythm of one or more of these factors may compromise the regularity of reproductive cycles.
is no longer detectable and changes in the average density of receptors is evident by the time animals are old. AGE-RELATED CHANGES IN THE ULTRADIAN RHYTHMS OF HORMONE SECRETION
AGE-RELATED CHANGES IN THE DIURNAL RHYTHM OF NEUROENDOCRINEACTIVITY
In female rats, as in human females, reproductive function declines during middle age. Female Sprague-Dawley rats become sexually mature between 1 and 2 months of age and exhibit regular 4- to 5-day estrous cycles. During middle age, at approximately 7-9 months of age, an increasing percent exhibit irregular cycles of 6--10 days in length. Finally, when rats are between 12 and 18 months of age, the majority become acyclic and exhibit constant vaginal estrus or persistent diestrus (17,18,33). We have previously reported that (a) norepinephrine is an important neuromodulator for release of GnRH (37); (b) a unique diurnal pattern of turnover rates exists in specific hypothalamic nuclei that are thought to regulate the cyclic release of LH on proestrus (37) and during steroid-induced LH surges (36,37,53); (c) middle-aged rats no longer exhibit this pattern of norepinephrine turnover in key regions of the hypothalamus (48,50). Most evidence supports the concept that norepinephrine's stimulatory effect on GnRH release is mediated by al-adrenergic receptors (10,16,23). Therefore, we have examined whether changes in the diurnal pattern of norepinephrine turnover are accompanied by changes in the density of cq-adrenergic receptors. We measured the density of a l receptors at multiple times of day in rats of different ages to determine (a) whether receptor densities exhibit a diurnal rhythm and (b) whether changes in receptor densities or the diurnal rhythm of their densities change during the middle-age period (47). Such changes could contribute to changes in the ability of aging animals to respond to adrenergic stimulation. Using autoradiographic methods, we found that the density of these receptors exhibit a diurnal rhythm in both the medial preoptic nucleus (see Fig. 1) and suprachiasmatic nucleus of young rats. Both of these brain regions are pacemaker areas and are involved in the maintenance of biological rhythms (5,7,35,43). In middle-aged rats, the diurnal rhythm in receptor density in these brain regions
GnRH secretion is pulsatile (6,29,30). The amplitude and frequency of GnRH pulses determines, in part, the amplitude and frequency of LH pulses (25,28). We reasoned that if changes in hypothalamic function occur during the initial stages of reproductive aging, we may be able to detect changes in the pulsatility of LH release. To assess whether chronological age and reproductive status of the animals interact to result in changes in GnRH release we used 4 experimental groups: young regularly cycling (2-3 months) and three groups of middle-aged (10-12 months) rats that were in various stages of reproductive senescence (41). The first group of middle-aged rats were regular cyclers at the time of ovariectomy, the second group of middle-aged rats were cycling irregularly at the time of ovariectomy, and the third middle-aged group had exhibited at least 14 consecutive days of cornified smears before they were ovariectomized. Rats exhibiting these stages of reproductive aging are known to have been exposed to different patterns of estradiol secretion. Because many investigators (3,4,27,32,34) have shown clearly that exposure to endogenously secreted or exogenously administered estrogen can modulate the rate of reproductive aging, dividing the middle-aged groups of rats into subgroups depending on reproductive status allowed us to evaluate the contribution of chronological versus reproductive age to changes in pulsatility. Various parameters of pulsatility change with chronological age and reproductive status: (a) amplitude decreased in all groups of middle-aged rats regardless of previous estrous cycle history; (b) changes in the responsiveness of the pituitary gland to GnRH stimulation are evident in middle-aged rats regardless of previous reproductive status; (c) pulse frequency, a more accurate indicator of hypothalamic function, decreased by the time middle-aged rats showed irregular estrous cycles but was not different from young rats if cycles were still regular at the time of ovariectomy (41). Further analysis of the frequency distribution of interpeak intervals in the four experimen-
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and ultradian oscillation are altered with age and may contribute to reproductive senescence (for reviews see 46,49,51). It is interesting to speculate that deterioration in a central element that influences these rhythms may occur during aging and may account for the seemingly unrelated changes that occur in rhythmic neural functions. The critical role of the suprachiasmatic nucleus, often considered the master oscillator or biological clock is well recognized. We hypothesized that if the timing of several neural events in the suprachiasmatic nucleus were altered with age, middle-aged rats would show a change in the circadian rhythm of local cerebral glucose utilization (LCGU), because this experimental endpoint reflects overall neural activity. In turn, age-related alterations in the rhythmicity of overall neural function may reflect a fundamental change in the circadian activity of the biological clock. We measured glucose utilization in this region of the brain using the 2-deoxy-D-1-14C glucose method with modifications that allowed us to assess glucose utilization in unrestrained rats (54). We found that in young rats, LCGU is elevated during the light period compared to the dark (Fig. 3). A unique aspect of the glucose rhythm in young rats is the secondary increase between 1000 hours and 1200 hours. This increase precedes the onset of the estradiolinduced LH surge and coincides with the increase in norepinephrine turnover. In middle-aged rats, although a circadian rhythm in glucose utilization is detectable, several notable differences exist. Glucose utilization rises more slowly after the lights go on and decreases prematurely during the afternoon prior to lights off. In addition, there is no secondary change during the morning; therefore glucose utilization is uniform during the entire light period and there is no increase preceding the time of the expected LH surge. The data suggest that aging involves a loss in the precision and/or synchrony of the timing of the diurnal rhythms or the activities of multiple neurotransmitters during middle age, thereby disrupting cyclic reproductive function. In summary, evidence supports the conclusions that (a) changes in hypothalamic function occur during the initial stages of reproductive aging and (b) subtle alterations that reflect changes in the integrity of the biological clock and the hypothalamic pulse generator or their ability to entrain rhythmic activity of multiple neurotransmitters occur during middle age and may be important elements in the cascade of events that leads to acyclicity and infertility in aged animals.
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animals that showed no deterioration in the regularity of their estrous cycles prior to ovariectomy. The data strongly suggest that changes in the hypothalamic pulse generator occur early during the transition to acyclicity and may play a key causative role in this age-related transition.
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tal groups revealed that the distributions of the interpeak intervals differ significantly in middle-aged rats before they show any change in estrous cyclicity. The dominant period exhibited by these middle-aged rats is the same as we observed in young rats; however, a smaller frequency of shorter interpeak intervals and a greater frequency of the longer periods between pulses occur when compared to young (Fig. 2). This shift toward longer interpeak intervals becomes more pronounced in middle-aged animals that
ACKNOWLEDGEMENTS This research was supported by NIH Grants AG-02224, AG-05357, HD-15955, and HD-07170. PMW is an NIH MERIT Awardee.
REFERENCES
1. Baird, D. T. Pulsatile secretion of LH and ovarian estradiol during the follicular phase of the sheep estrous cycle. Biol. Reprod. 18:359-364; 1978. 2. Blake, C. A.; Sawyer, C. H. Effects of hypothalamic deafferentation on the pulsatile rhythm in plasma concentrations of luteinizing hormone in ovariectomized rats. Endocrinol. 94:730-736; 1974.
3. Brawer, J. R.; Naftolin, F.; Martin, J.; Sonnenschein, C. Effects of a single injection of estradiol valerate on the hypothalamic arcuate nucleus and on reproductive function in the female rat. Endocfinol. 103:501-512; 1978. 4. Brawer, J. R.; Ruf, K. B.; Naftolin, F. The effects of estradiolinduced lesions of the arcuate nucleus on gonadotropin release in
506
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17. 18. 19.
20. 21.
22.
23.
24.
25.
26.
response to preoptic stimulation in the rat. Neuroendocrinol. 30:144149; 1980. Brown-Grant, K.; Raisman, G. Abnormalities in reproductive function associated with the destruction of the suprachiasmatic nuclei in female rats. Proc. R. Soc. Lond. B. 198:279-296; 1977. Cannel, P. W.; Araki, S.; Ferin, M. Pituitary stalk portal blood collection in rhesus monkeys: evidence for pulsatile release of gonadotropin-releasing hormone (GnRH). Endocrinol. 99:243-248; 1976. Coen, C. W.; MacKinnon, P. C. B. Lesions of the suprachiasmatic nuclei and the serotonin-dependent phasic release of luteinizing hormone in the rat: Effects on drinking rhythmicity and on the consequences of preoptic area stimulation. J. Endocr. 84:231-236; 1980. Coombs, M. C.; Coen, C. W. Adrenaline turnover rates in the medial preoptic area and mediobasal hypothalamus in relation to the release of luteinizing hormone in female rats. Neurosci. 10:207-210; 1983. Dierschke, D. J.; Bhattacharya, A. N.; Atkinson, L. E.; Knobil, E. Circhoral oscillations of plasma LH levels in the ovariectomized rhesus monkey. Endocrinol. 87:850--853; 1970. Drouva, S. V.; Laplante, E.; Kordon, C. alphal-Adrenergic receptor involvement in the LH surge in ovariectomized estrogen-primed rats. Eur. J. Pharmacol. 81:341-344; 1982. Everett, J. W.; Sawyer, C. H. A 24-hour periodicity in the "LHrelease apparatus" of female rats, disclosed by barbiturate sedation. Endocrinol. 47:198-218; 1950. Everett, J. W.; Sawyer, C. H.; Markee, J. E. A neurogenic timing factor in control of the ovulatory discharge of luteinizing hormone in the cyclic rat. Endocrinol. 44:234-250; 1949. Filicori, M.; Santoro, N.; Merriam, G. R.; Crowley, W. F., Jr. Characterization of the physiological pattern of episodic gonadotropin secretion throughout the human menstrual cycle. J. Clin. Endocrinol. Metab. 62:1136-1144; 1986. Fox, S. R.; Smith, M. S. Changes in the pulsatile pattern of luteinizing hormone secretion during the rat estrous cycle. Endocrinol. 116: 1485-1492; 1985. Gray, G. D.; Sodersten, P.; Tallentire, D.; Davidson, J. M. Effects of lesions in various structures of the suprachiasmatic-preoptic region on LH regulation and sexual behavior in female rats. Neuroendocrinol. 25:174-191; 1978. Heaulme, M.; Dray, F. Noradrenaline and prostaglandin E2 stimulate LH-RH release from rat median eminence through distinct l-alphaadrenergic and PGE 2 receptors. Neuroendocrinol. 39:403-407; 1984. Huang, H. H.; Meites, J. Reproductive capacity of aging female rats. Neuroendocrinol. 17:289-295; 1975. Ingram, D. L. The vaginal smear of senile laboratory rats. J. Endocr. 19:182-188; 1959. Jarry, H.; Leonhardt, S.; Wuttke, W. A norepinephrine dependent mechanism in the preoptic/anterior hypothalamic area is involved in regulation of the GnRH pulse generator in ovariectomized rats. Neuroendocrinol. 1989. Kafka, M. S.; Marangos, P. J.; Moore, R. Y. Suprachiasmatic nucleus ablation abolishes circadian rhythms in rat brain neurotransmitter receptors. Brain Res. 327:344-347; 1985. Kalra, S. P. Catecholamine involvement in preovulatory LH release: reassessment of the role of epinephrine. Neuroendocrinol. 40:139144; 1985. Karsch, F. J. Central actions of ovarian steroids in the feedback regulation of pulsatile secretion of luteinizing hormone. Ann. Rev. Physiol. 49:365-382; 1987. Kaufman, J.-M.; Kesner, J. S.; Wilson, R. C.; Knobil, E. Electrophysiological manifestation of luteinizing hormone-releasing hormone pulse generator activity in the rhesus monkey: influence of alphaadrenergic and dopaminergic blocking agents. Endocrinol. 116:13271333; 1985. Kawakami, M.; Arita, J.; Yoshioka, E. Loss of estrogen-induced daily surges of prolactin and gonadotropins by suprachiasmatic nucleus lesions in ovariectomized rats. Endocrinol. 106:1087-1092; 1980. Kesner, J. S.; Wilson, R. C.; Kaufman, J.-M.; Hotchkiss, J.; Chen, Y.; Yamamoto, H.; Pardo, R. R.; Knobil, E. Unexpected responses of the hypothalamic gonadotropin-releasing hormone "pulse generator" to physiological estradiol inputs in the absence of the ovary. Proc. Natl. Acad. Sci. USA 84:8745-8749; 1987. Krey, L. C.; Butler, W. R.; Knobil, E. Surgical disconnection of the
W I S E ET AL.
27.
28.
29.
30. 31.
32.
33. 34.
35.
36.
37.
38.
39.
40. 41.
42. 43.
44. 45. 46. 47.
medial basal hypothalamus and pituitary function in the rhesus monkey. I. Gonadotropin secretion. Endocrinol. 96:1073-1087; 1975 (Abstract). Lapolt, P. S.; Matt, D. W.; Judd, H. L.; Lu, J. K. H. The relation of ovarian steroid levels in young female rats to subsequent estrous cyclicity and reproductive function during aging. Biol. Reprod. 35: 1131-1139; 1986. Levine, J. E.; Duffy, M. T. Simultaneous measurement of luteinizing hormone (LH)-releasing hormone, LH, and follicle-stimulating hormone release in intact and short-term castrate rats. Endocrinol. 122: 2211-2221; 1988. Levine, J. E.; Norman, R. L.; Gliessman, P. M.; Oyama, T. T.; Bangsberg, D. R.; Spies, H. G. In vivo gonadotropin-releasing hormone release and serum luteinizing hormone measurements in ovariectomized, estrogen-treated rhesus macaques. Endocrinol. 117:711721; 1985. Levine, J. E.; Powell, K. D. Microdialysis for measurement of neuroendocrine peptides. Meth. Enzymol. 168:166-181; 1989. Lincoln, D. W.; Fraser, H. M.; Lincoln, G. A.; Martin, G. B.; McNeilly, A. S. Hypothalamic pulse generators. Rec. Prog. Hormone Res. 41:369-419; 1985. Lu, J. K. H.; Lapolt, P. S.; Nass, T. E.; Matt, D. W.; Judd, H. L. Relation of circulating estradiol and progesterone to gonadotropin secretion and estrous cyclicity in aging female rats. Endocrinol. 116: 1953-1959; 1985. Mandl, A. M. Cyclic changes in the vaginal smears of senile nulliparous and multiparous rats. J. Endocr. 22:257-268; 1961. Naftolin, F.; MacLusky, N. J.; Leranth, C. Z.; Sakamoto, H. S.; Garcia-Segura, L. M. The cellular effects of estrogens on neuroendocrine tissues. J. Steroid Biochem. 29:215-228; 1988. Raisman, G.; Brown-Grant, K. The 'suprachiasmatic syndrome': endocrine and behavioural abnormalities following lesions of the suprachiasmatic nuclei in the female rat. Proc. R. Soc. Lond. B. 198:297314; 1977. Rance, N.; Wise, P. M.; Barraclough, C. A. Negative feedback effects of progesterone correlated with changes in hypothalamic norepinephrine and dopamine turnover rates, median eminence luteinizing hormone-releasing hormone, and peripheral plasma gonadotropins. Endocrinol. 108:2194-2199; 1981. Rance, N.; Wise, P. M.; Selmanoff, M. K.; Barraclough, C. A. Catecholamine turnover rates in discrete hypothalamic areas and associated changes in median eminence luteinizing hormone-releasing hormone and serum gonadotropins on proestrus and diestrous day 1. Endocrinol. 108:1795-1802; 1981. Rasmussen, D. D. Physiological interactions of the basic rest-activity cycle of the brain: pulsatile luteinizing hormone secretion as a model. Psychoneuroendocrinol. 11:389--405; 1986. Santoro, N.; Butler, J. P.; Filicori, M.; Crowley, W. F., Jr. Alterations of the hypothalamic GnRH interpulse interval sequence over the normal menstrual cycle. Am. J. Physiol. 255:E696-E701; 1988. Sawyer, C. H.; Everett, J. W.; Markee, J. E. A neural factor in the mechanism by which estrogen induces the release of luteinizing hormone in the rat. Endocrinol. 44:218-233; 1949. Scarbrough, K.; Wise, P. M. Age-related changes in the pulsatile pattern of LH release precede the transition to estrous acyclicity and depend upon estrous cycle history. Endocrinol. 126:884-890; 1990. Seibel, M. M.; Shine, W.; Smith, D. M.; Taymor, M. L. Biological rhythm of the luteinizing hormone surge in women. Fertil. Steril. 37:709-711; 1982. Szafarczyk, A.; Ixart, G.; Malaval, F.; Nouguier-Soule, J.; Assenmacher, I. Effects of lesions of the suprachiasmatic nuclei and of p-chlorophenylalanine on the circadian rhythms of adrenocorticotrophic hormone and corticosterone in the plasma, and on locomotor activity of rats. J. Endocr. 83:1-16; 1979. Testart, J.; Frydman, R.; Roger, M. Seasonal influence of diurnal rhythms in the onset of the plasma luteinizing hormone surge in women. J. Clin. Endocrinol. Metab. 55:374-377; 1982. Walker, R. F. Reinstatement of LH surges by serotonin neuroleptics in aging, constant estrous rats. Neurobiol. Aging 3:253-257; 1982. Walker, R. F. Impact of age-related changes in serotonin and norepinephrine metabolism on reproductive function in female rats: an analytical review. Neurobiol. Aging 5:121-139; 1984. Wetland, N. G.; Wise, P. M. Aging progressively alters the diurnal
DIURNAL AND PULSATILE RHYTHMS
48. 49, 50.
51.
rhythms and decreases the densities of alpha- 1-adrenergic receptors in selected hypothalamic regions. Endocrinol. 126:2392-2397; 1990. Wise, P. M. Norepinephrine and dopamine activity in microdissected brain areas of the middle-aged and young rat on proestrus. Biol. Reprod. 27:562-574; 1982. Wise, P. M. Aging of the female reproductive system. Rev. Biol. Res. Aging 1:195-222; 1983. Wise, P. M. Estradiol-induced daily luteinizing hormone and prolactin surges in young and middle-aged rats: Correlations with agerelated changes in pituitary responsiveness and catecholamine turnover rates in microdissected brain areas. Endocrinol. 115:801-809; 1984. Wise, P. M. Aging of the female reproductive system: A neuroendo-
507
crine perspective. In: E. E. Muller and R. M. MacLeod, eds. Neuroendocrine perspectives, Vol. 7. New York: Springer-Verlag; 1989: 117-168. 52. Wise, P. M.; Cohen, I. R.; Weiland, N. G.; London, E. D. Aging alters the circadian rhythm of glucose utilization in the suprachiasmatic nucleus. Proc. Natl. Acad. Sci. USA 85:5305-5309; 1988. 53. Wise, P. M.; Rance, N.; Barraclough, C. A. Effects of estradiol and progesterone on catecholamine turnover rates in discrete hypothalamic regions in ovariectomized rats. Endocrinol. 108:2186--2193; 1981. 54. Wise, P. M.; Walovitch, R. C.; Cohen, I. R.; Weiland, N. G.; London, E. D. Diurnal rhythmicity and hypothalamic deficits in glucose utilization in aged ovariectomized rats. J. Neurosci. 7:3469-3473; 1987.