Biology of Reproduction 63, 968-976 (2000)
© 2000 Society for the Study of Reproduction, Inc.
Hypothalamic Alterations and Reproductive Aging in Female Rats: Evidence of Altered Luteinizing Hormone-Releasing Hormone Neuronal Function1
Beverly S. Rubin2,a
a Department of Anatomy and Cellular Biology, Tufts Medical School, Boston, Massachusetts 02111
 |
ABSTRACT
|
|---|
Prior to the age-related loss of regular estrous cycles, female rats exhibit an attenuated preovulatory LH surge, a sign that reproductive decline is imminent. Numerous studies have revealed an important role for the hypothalamus in aging of the reproductive axis in this species. Because LHRH represents the primary hypothalamic signal that regulates gonadotropin release, assessments of LHRH neuronal activity can provide a window into hypothalamic function during reproductive aging. Studies of the dynamic activity of LHRH neurons during times of enhanced secretion have revealed deficits in middle-aged females. Available data are consistent with a decline in LHRH synthesis, transport, and secretion in middle-aged females during times of increased demand for LHRH output. Moreover, the alterations noted in LHRH neuronal function could account, in part, for the attenuation and eventual loss of the preovulatory LH surge with age. Elements extrinsic to LHRH neurons undoubtedly contribute to the decline in the parameters of LHRH neuronal function observed in middle-aged females. Whether alterations intrinsic to LHRH neurons also play a role in the age-associated reduction in LHRH synthesis and secretion remains to be determined. Recent examinations of hormone profiles during the perimenopausal period suggest that a potential hypothalamic contribution to aging of the reproductive axis in women warrants further examination.
aging, GnRH, hypothalamus, LH, ovulation
|
REGULAR ESTROUS CYCLES CEASE RELATIVELY EARLY IN THE LIFE SPAN OF FEMALE RATS
|
|---|
Age-associated deficits are detected in the hypothalamic-pituitary-ovarian axis of many female mammals prior to the time that the effects of aging are evident in other systems. The age-related reproductive decline has been particularly well characterized in female rodents [1–3], including rats that will be the focus of this minireview. Female rats cease exhibiting regular estrous cycles at approximately 9–12 mo of age, with the loss of estrous cyclicity occurring earlier in nulliparous relative to multiparous and primiparous females [4]. As female rats age, regular 4- to 5-day estrous cycles gradually transition to irregular estrous cycles that typically include elongated cycles interspersed with normal cycles [2, 5]. The elongated cycles are most often characterized by extended periods of vaginal cornification, suggesting periods of sustained estrogen secretion and delayed ovulation. Eventually, animals enter into a chronic anovulatory state that in many rat strains is characterized by persistent vaginal cornification, often referred to as persistent estrus. The ovaries of persistent estrous animals contain follicles in various stages of development and no corpora lutea because spontaneous ovulation has ceased [4, 5].
Prior to the age-related loss of regular estrous cycles, middle-aged (this term is generally used to refer to animals between 8 and 14 mo of age) female rats exhibit an attenuation and, in many cases, a delay of the preovulatory LH surge [6–8]. Following ovariectomy, the hypersecretion of LH and the steroid-induced LH surge are also diminished in middle-aged relative to young females [9], further documenting an age-associated decrease in circulating LH titers at times of enhanced LH secretion. Alterations in circulating ovarian steroid levels have also been observed in regularly cycling middle-aged female rats [6]; most significant may be the age-related elevation in estradiol levels. This exposure to increased levels of estradiol over successive estrous cycles may gradually decrease neuroendocrine responsiveness to the positive feedback effects of estradiol on LH secretion [1, 4, 5]. As middle-aged females enter into prolonged periods of vaginal cornification and eventually cease exhibiting spontaneous ovulation, circulating progesterone levels remain low. The resulting increase in the estradiol:progesterone ratio may further contribute to deterioration of hypothalamic-pituitary-ovarian axis function [1, 10].
|
THE HYPOTHALAMUS IS AN IMPORTANT SITE OF DEFICIT FOR REPRODUCTIVE AGING
|
|---|
Age-related alterations at all levels of the reproductive axis have been documented and undoubtedly contribute to the cascade of events that lead to reproductive decline in female rats. Much debate has centered on the relative contributions of age-associated changes at the ovary and at the hypothalamic-pituitary levels to the loss of fertility. Due to the intimate inter-relationships and interactions that exist between the various levels of the reproductive axis, these distinctions are not easily delineated. Alterations in ovarian activity can influence hypothalamic function, hypothalamic-pituitary changes can impact the ovary, and hypothalamic alterations can influence pituitary function.
Data from studies in women [11], rats [10, 12, 13], and mice [14] reveal a decline in follicle number in the ovary with age and suggest that this decline plays a role in reproductive aging. Clearly oocytes show evidence of aging [15]. Follicular development, follicular dynamics, and hormonal profiles also change with age in the rat ovary [16, 17], and these changes may influence or accelerate aging of the reproductive axis.
Age-related changes in pituitary function have also been demonstrated [18–23]. In vitro studies have revealed a diminished response of perifused pituitaries [18] or dispersed pituitary cells [19] from middle-aged female rats to GnRH stimulation, and an age-related alteration in the protein synthesis-dependent phase of LH secretion in female mouse pituitaries [23]. An attenuation of pituitary gonadotropin subunit gene expression in middle-aged relative to young female rats has also been documented in conjunction with the LH surge and following ovariectomy [20, 21].
Whereas ovarian and pituitary alterations undoubtedly contribute to aging of the reproductive axis, data from numerous experimental paradigms suggest the primary importance of the hypothalamus to the age-related reproductive decline in female rats. Although studies in women demonstrate that menopause is associated with the exhaustion of primordial follicles in the ovary [24], studies in rats reveal that follicular exhaustion is not apparent at the time that regular estrous cycles are lost [12, 13]. Early transplant studies demonstrated that ovaries of aging acyclic rats could support estrous cyclicity when transplanted into young females [25, 26]. In contrast, aging acyclic females remained acyclic after receiving young ovary transplants, suggesting the importance of hypothalamic-pituitary deficits to the age-related disruption of estrous cycles. Data from subsequent transplant studies in mice [27] further characterized the role of the ovary and documented neuroendocrine contributions to aging of the hypothalamic-pituitary-ovarian axis. The temporary restoration of function to the reproductive axis of aging acyclic female rats by electrical stimulation of the hypothalamus or administration of centrally acting drugs provided compelling evidence of the importance of the hypothalamus to reproductive aging in this species [4, 28, 29].
|
LHRH IS THE PREDOMINANT HYPOTHALAMIC SIGNAL THAT MODULATES GONADOTROPIN SECRETION
|
|---|
Luteinizing hormone-releasing hormone, also known as GnRH, is the predominant hypothalamic signal responsible for the modulation of synthesis and secretion of pituitary gonadotropins and is essential for steroidogenesis and follicular development in the ovary. The parameters of LHRH secretion at any given time reflect the balance of a complex array of excitatory and inhibitory influences originating in the hypothalamus and other regions of the brain and brainstem that influence activity within the population of LHRH neurons [30, 31]. Feedback loops involving the ovaries [32, 33], the pituitary [34], and LHRH itself [35–37] are all involved in the complex regulation of these neurons. Of particular relevance to aging females is the exquisite orchestration of the myriad of signals required for induction of the LHRH/LH surge required for ovulation [38].
As discussed, deficits at the hypothalamic level are important to reproductive aging in female rats. Because LHRH represents the primary hypothalamic signal regulating pituitary gonadotropin secretion, assessments of LHRH neuronal activity in middle-aged females can provide a valuable window into hypothalamic function at the time of reproductive decline. The results of studies of LHRH activity in middle-aged females during times of enhanced LHRH secretion are reviewed below.
|
THE POPULATION OF NEUROENDOCRINE LHRH NEURONS AND CONSIDERATIONS FOR AGING STUDIES
|
|---|
The diffuse organization of LHRH cell bodies across several brain nuclei including the preoptic area, septal nuclei and hypothalamus [39, 40] complicates the study of LHRH neuronal function in aging females. The dispersed localization of the estimated 1200–1600 neuroendocrine LHRH neurons may help to ensure reproductive success by maximizing the information these neurons receive from the internal and external environment. However, this diffuse organization impedes the use of many protocols suitable for examination of discretely localized peptidergic neurons. In addition to modulation at the level of LHRH cell bodies, influences exerted at LHRH terminals in the median eminence, the site of LHRH release, are also important for the regulation of LHRH secretion [41].
Adding to the complexity of the examination of LHRH neuronal activity in aging females is the functional heterogeneity of the population of LHRH neurons [42, 43]. Specific subgroups of LHRH neurons may be particularly important for triggering the preovulatory LH surge, whereas others may not be essential for or may not be involved in LH surge induction. Examples of the heterogeneity of the population of LHRH neurons are revealed by the demonstration that subsets of the population of LHRH neurons and not the entire population 1) receive direct projections from the suprachiasmatic nucleus (SCN) [44, 45] 2) colocalize immediate early genes in their nuclei in conjunction with an LH surge [46–48]; 3) colocalize the peptide galanin [49–51]; and 4) express detectable levels of N-methyl-D-aspartate (NMDA) R1 receptors [52]. Failure to consider the functional heterogeneity of the population of LHRH neurons may mask age-related changes within specific subgroups important for LH surge induction [53, 54], and these subgroups may be most affected in middle-aged females. Moreover, recent evidence suggests that small changes within the population of LHRH neurons or subgroups of the population may be sufficient to power the LH surge [55].
|
ASSESSMENTS OF LHRH NEURONAL FUNCTION
|
|---|
There are several factors of potential significance when considering a role for altered LHRH neuronal function in the loss of estrous cyclicity with age. First, LHRH release is pulsatile and the precise parameters of pulsatile LHRH release modulate synthesis and secretion of pituitary gonadotropins. In general, slowing of pulsatile LHRH release favors FSH and increased LHRH pulse generation favors LH synthesis and secretion [56, 57]. Pulsatile LHRH release directly influences the sensitivity of the pituitary to LHRH by modulating the density of pituitary LHRH receptors [58, 59]. Despite the importance of the precise parameters of pulsatile LHRH release to reproductive fertility, the nature of the LHRH pulse generator is not yet understood. Recordings of hypothalamic multiunit activity in monkeys suggest the existence of a hypothalamic signal generator that directs pulsatile release of LHRH [60, 61]. In addition, there is mounting evidence that LHRH pulse generation may be intrinsic to LHRH neurons. Immortalized LHRH neurons release LHRH in a pulsatile manner [62, 63] as do cultured fetal rat hypothalamic cells [64] and enzymatically dispersed rat hypothalamic explants [65]. Moreover, LHRH neurons present in olfactory placode explants from embryonic rhesus monkeys exhibit pulsatile LHRH release [66] with a pulse frequency similar to that measured in adult monkeys in vivo [31]. These data have led to the hypothesis that LHRH neurons may possess an endogenous pulse-generating mechanism that is in turn modulated by neuronal and non-neuronal inputs [31, 67].
Also potentially relevant to the study of aging females is evidence suggesting that LHRH neurons possess the potential for high biosynthetic capacity [55] that may be obligatory for generation of the preovulatory LH surge. Data from hypothalamic explant studies [68] have demonstrated that LHRH neurons exhibit a high level of LHRH mRNA turnover. Other studies in rodents reveal that LHRH neurons express a high copy number of LHRH mRNA [55]. A high percentage of LHRH RNA exists as primary transcripts in the nucleus [69, 70], suggesting a high level of transcriptional activity in these neurons. Furthermore LHRH neurons can reportedly maintain a high rate of peptide synthesis [55]. The normally high levels of gene transcription in LHRH neurons may be further increased in conjunction with the preovulatory [71] and steroid-induced LH surges [72] when synthesis and secretion of LHRH are greatly enhanced. As discussed previously, immediate early gene expression [46–48] and galanin gene expression [49–51] are also induced within a subset of the population of LHRH neurons in conjunction with the LH surge.
Alterations in several parameters of LHRH neuronal function have been documented in middle-aged relative to young females in conjunction with the spontaneous LH surge on proestrus and the steroid-induced LH surge [73–79]. Both are times of heightened LHRH neuronal activity. In contrast, examination of the population of LHRH neurons during more static times with regard to LHRH activity failed to reveal significant age-related differences [80], indicating that age-associated differences in LHRH neuronal function are most pronounced during times of increased demand on the population LHRH neurons.
LHRH Output in Middle-Aged Females
Assessments of in vivo LHRH output in young and middle-aged females in conjunction with a steroid-induced LH surge [75] using push-pull perfusion protocols [81] revealed an age-related decrease in LHRH secretion. The number of LHRH pulses detected in effluents from middle-aged females during the perfusion period was decreased relative to young females, indicative of an age-associated decrease in LHRH pulse generation. The decrease in mean LHRH output and in LHRH pulse frequency suggests that the attenuated LH surge observed in middle-aged females may reflect diminished LHRH release (see Fig. 1).
View larger version (51K):
[in this window]
[in a new window]
|
FIG. 1. Measurements of in vivo LHRH output in the medial basal hypothalamus and serum LH levels on the day of a steroid-induced LH surge in ovariectomized young and middle-aged females. At the time of ovariectomy, the young females were 3–4 mo old and the middle-aged females were 10–12 mo old. As depicted, the overall mean levels of LHRH output were significantly lower in middle-aged relative to young females, and the mean number of LHRH pulses detected during the period of perfusion was also diminished in middle-aged females. It is likely that the decline in LHRH release contributed to the attenuated peak levels of serum LH that were measured in conjunction with the LH surge in middle-aged relative to young females. Adapted from Rubin and Bridges [75]; *P < 0.05; ***P < 0.001
|
|
Indirect evidence of an age-related decline in pulsatile LHRH release has also been observed in ovariectomized females [82]. Serum LH measurements in middle-aged and young ovariectomized females provided evidence of changing pulse generator function with age. The changes were most pronounced in middle-aged females that were not cycling regularly prior to ovariectomy; however, middle-aged females that were regularly cycling prior to ovariectomy also exhibited longer intervals between LH pulses and a decrease in LH pulse amplitude relative to young females. These data indicate that altered LHRH pulse generation preceded the loss of estrous cyclicity. The altered pattern of pulsatile LH release in middle-aged females was presumed to reflect changes in LHRH pulse generator activity that was postulated to play a role in the age-related transition to acyclicity.
Pituitary Data Provide Indirect Evidence of Altered LHRH Secretion with Age
Other indirect evidence consistent with diminished LHRH output in middle-aged females may be gleaned from studies of gonadotropin subunit and LHRH receptor gene expression in the pituitary that are known to be regulated by pulsatile LHRH release [56–59]. The decline in pituitary LHRH receptor mRNA levels in middle-aged females on the day of a steroid-induced LH surge [83] and in maximal LHRH binding capacity on the morning of proestrus [84] are consistent with an age-related decline in pulsatile LHRH release. Decreased LHRH receptor density would diminish pituitary sensitivity to LHRH that could, in turn, contribute to the attenuation of the LH surge. Several studies have revealed decreased pituitary responsiveness to LHRH administration in middle-aged females [18, 20, 82, 85]. Decreased gonadotropin subunit gene expression has also been noted in the pituitaries of middle-aged females in conjunction with the preovulatory [20] and steroid-induced LH surge [83] and during the rise in circulating LH levels following ovariectomy [21].
Although levels of LHRH receptor and gonadotropin subunit gene expression in the pituitary are consistent with altered patterns of LHRH secretion, the potential contribution of intrinsic deficits at the pituitary level must be acknowledged. As discussed, pituitary deficits have been reported with age in rodents [18, 19, 23], and the relative contributions of intrinsic pituitary deficits and altered parameters of LHRH output in these studies are not easily resolved.
Patterns of LHRH Immunoreactivity Differ in Young and Middle-Aged Females on Proestrus
Immunocytochemical studies have demonstrated dynamic changes in the detectability of LHRH cell bodies prior to and after the preovulatory LH surge on proestrus in young but not middle-aged females [76]. The dynamic changes and the age-related deficits were most pronounced in specific regions of the population of LHRH neurons. Computer-assisted image analysis of the levels of LHRH immunoreactivity in terminal regions in the median eminence also revealed age-related differences [86]. A pattern of immunoreactivity consistent with accumulation of LHRH in the median eminence prior to the start of the LH surge and depletion of LHRH after the peak of the LH surge was observed in young females but was not apparent in middle-aged females. Measurements of LHRH levels in median eminence extracts have also demonstrated the failure of middle-aged females to accumulate LHRH in the median eminence prior to the LH surge on proestrus [7].
The dynamic changes in LHRH immunoreactivity observed in young females are consistent with 1) the transport of LHRH from cell bodies to terminals and the accumulation of LHRH in the median eminence prior to the start of the LH surge, 2) the depletion of LHRH stores in the median eminence during the LH surge, and 3) new synthesis of LHRH after the peak of the LH surge. Therefore, the available data suggest increased LHRH neuronal activity in young but not middle-aged females in conjunction with the preovulatory LH surge.
LHRH/Fos Colocalization Suggests an Age-Related Decline in Activated LHRH Neurons
Fos expression has been noted within LHRH neurons in conjunction with the spontaneous or steroid-induced LH surge [46, 48]. Although the role of Fos within LHRH neurons is not known, the presence of Fos protein in the nucleus of LHRH neurons is presumed to provide one index of LHRH neuronal activation. Comparisons of Fos induction in LHRH neurons of young and middle-aged regularly cycling females on the day of proestrus (see Fig. 2) revealed a diminished level of colocalization within middle-aged relative to young females [73, 77, 78]. The age-related differences were pronounced in specific regions of the population [78]. Studies of ovariectomized, steroid-primed females confirmed that the age-related deficit was not due to potential differences in circulating steroid levels [77]. The decline in LHRH/Fos colocalization indicates that a decreased percentage of LHRH neurons are activated in middle-aged relative to young females in conjunction with an LH surge. This decline in the number of activated LHRH neurons could contribute to the attenuation and eventual loss of the preovulatory LH surge in aging female rats. Reduced colocalization of another immediate early gene, cJun, within LHRH neurons in middle-aged females on proestrus [73], provides an additional marker of age-related change within the population of LHRH neurons.
View larger version (93K):
[in this window]
[in a new window]
|
FIG. 2. A coronal view of three-dimensional reconstructions of the population of LHRH neurons in the brains of young (3–4 mo old [A]) and middle-aged (9–11 mo old [B]) female rats during the early ascending phase of the LH surge on proestrus. Each reconstruction represents a compilation of data from every fourth 50-µm section through the brain of four different animals. Black triangles represent the location of the single-labeled LHRH neurons, and the white triangles represent LHRH neurons that contain Fos protein in the nucleus. As depicted, a lower percentage of LHRH neurons exhibit Fos induction in middle-aged relative to young females, indicating decreased activation of the population of LHRH neurons at this time. Overall cell counts revealed that approximately 10% of all LHRH neurons in the brains of middle-aged and approximately 28% of all LHRH neurons in the brains of young females exhibited Fos induction at this time point. The majority of double-labeled LHRH neurons were located in the center of the population, which is well represented in this single coronal view of the reconstruction. A lower percentage of LHRH neurons in rostral, caudal, or lateral aspects of the population colocalized Fos protein. Adapted from Rubin et al. [78]
|
|
LHRH Gene Expression Is Diminished in Middle-Aged Females
As discussed previously, dynamic changes in LHRH mRNA levels have been noted within the population of LHRH neurons in conjunction with the preovulatory LH surge on proestrus [53, 71, 87, 88] and with the steroid-induced LH surge [54, 72] and may reflect changes in LHRH gene transcription [53, 72]. Assessments of LHRH mRNA levels by in situ hybridization revealed age-related differences on the day of a steroid-induced LH surge [79]. Dynamic changes in the number of LHRH mRNA-positive cells were observed over time in the preoptic area of young but not middle-aged females. Moreover, the number of LHRH mRNA positive neurons was significantly lower in middle-aged relative to young females at the start of the LH surge. Detailed analysis of LHRH mRNA-positive cells in sections through the rostral preoptic area revealed an age-related decrease in LHRH mRNA levels per cell and per region. Decreased LHRH mRNA levels could limit the level of new LHRH biosynthesis that might be important for generation of the LH surge. Decreased LHRH mRNA levels have also been observed in aging male rats [89, 90].
Deficits Extrinsic to LHRH Neurons Contribute to Altered LHRH Neuronal Function
The data reviewed provide evidence of compromised LHRH neuronal function in middle-aged relative to young females during times of increased LHRH output. The suboptimal levels of LHRH activity reported may be expected to contribute to attenuation and eventual loss of the preovulatory LH surge. The cause of the progressive age-related decline in LHRH neuronal function remains inadequately defined. As mentioned, the regulation of LHRH neuronal function is complex and many putative modulators of LHRH synthesis and secretion have been identified [30, 31]. It is clear that the induction of the LH surge requires increased excitatory signals, restraint of inhibitory signals, and appropriate input from the SCN [38].
Alterations in putative excitatory influences on LHRH secretion have been documented in middle-aged animals and could contribute to alterations in LHRH synthesis and secretion with age. For example, the lower levels of norepinephrine turnover [91], neuropeptide Y gene expression and secretion [92], or nitric oxide synthase gene expression [93] observed in middle-aged relative to young females may contribute to the age-related decrease in LHRH neuronal function in conjunction with LH surge induction. A diminished responsiveness to signals excitatory to LHRH release has also been reported in middle-aged females. Following stimulation with various excitatory amino acid agonists, significantly less LHRH was released from hypothalamic fragments of regularly cycling middle-aged relative to young proestrous females [94]. The release data coupled with measurements of an age-related decline in NMDA R1 receptor levels suggest that decreased responsiveness to excitatory amino acids may contribute to the decline in LHRH neuronal function with age. On a more general level, positive feedback effects of estrogen on LHRH/LH release may be impaired due to age-related alterations in estrogen receptor dynamics [95, 96].
Other potentially significant age-related alterations extrinsic to LHRH neurons include changes in the function of the SCN, which is important for the LH surge in rodents [97, 98]. The SCN may indirectly influence LHRH neurons via projections to interneurons that in turn project to LHRH neurons and by regulating rhythms of hypothalamic neurotransmitters and neuropeptides important for LH surge induction [99]. Age-related changes in neurotransmitter and neuropeptide rhythms have been documented in the SCN [100], and an age-related decrease in Fos induction in response to light has also been observed [101]. It is likely that these age-related changes may affect the integrity of SCN function and therefore potentially interfere with events important for the induction of the LH surge. Particularly intriguing are the direct projections from the SCN that reportedly contact LHRH neurons [44, 45]. More specifically, vasoactive intestinal peptide (VIP)-synthesizing neurons in the SCN project to a subset of LHRH neurons that may be important for triggering the LH surge [102]. Data from a study that interfered with the synthesis of VIP in the SCN [103] are consistent with a role for VIP in LH surge induction. Therefore the age-related alteration in rhythmic expression of VIP mRNA observed in the SCN of female rats [104] could be expected to impact negatively the LHRH/LH surge.
Do Alterations Intrinsic to LHRH Neurons Play a Role in Reproductive Decline?
Whereas alterations extrinsic to LHRH neurons may be sufficient to explain the age-related changes in LHRH neuronal function, the possibility that age-related alterations intrinsic to LHRH neurons contribute to the decline in LHRH/LH release has been relatively unexplored. Because LHRH pulsatility may be intrinsic to LHRH neurons [31, 67], it is conceivable that pulsatile LHRH release may slow with aging. As mentioned, there is some evidence of slowing of LHRH pulse generation with age in rats [75, 82].
Another consideration with regard to the involvement of alterations intrinsic to LHRH neurons in reproductive aging is their potential for high biosynthetic capacity that may be mandatory for generation of the preovulatory LH surge [55]. As mentioned previously, LHRH neurons exhibit a high copy number of LHRH mRNA [55], rapid turnover of LHRH mRNA [68], high levels of LHRH primary transcript [69, 70], and are capable of maintaining a high rate of peptide synthesis [55]. Moreoever, there is evidence of increased gene expression within LHRH neurons in conjunction with the LH surge [46, 48–51, 53, 71, 72, 79, 87, 88]. High levels of cellular activity are associated with increased energy requirements. Is it possible that aging LHRH neurons can no longer maintain adequate energy reserves to accommodate the increased activity associated with induction of the preovulatory LH surge? Metabolic challenges such as caloric restriction and restriction of glucose availability are known to disrupt estrous cyclicity and supress pulsatile LH release in many species [105–109], and the ability of LHRH or LHRH secretagogues to restore circulating LH levels indicates neuroendocrine involvement in the LH suppression [105, 108–110]. The inhibition of cellular glucose oxidation by intracranial administration of 2-deoxy-D-glucose (2DG) attenuated the steroid-induced LH surge in young ovariectomized female rats [111]. Moreover, the treatment significantly decreased the number of LHRH neurons that expressed Fos protein, suggesting that the inhibition of cellular glucose oxidation was correlated with alterations in the activation of LHRH neurons. Although the effects of 2DG administration in the study were clearly not restricted to LHRH neurons [111], it is interesting to note that the response of young females to the inhibition of glucose utilization resembles the attenuation of the LH surge and the diminished LHRH/Fos colocalization observed in middle-aged female rats [73, 77, 78].
To date there is no evidence of significant loss of LHRH neurons at the time that estrous cyclicity is disrupted. However, the number of detectable LHRH neurons is reportedly decreased by old age in rats and mice [112, 113]. Is it possible that the loss of specific LHRH neurons critical for triggering the LH surge contributes to the attenuation and eventual loss of the preovulatory LH surge with age?
|
DO HYPOTHALAMIC ALTERATIONS CONTRIBUTE TO MENOPAUSE?
|
|---|
The regulation of estrous cycles and menstrual cycles differ in many ways, and different mechanisms are undoubtedly involved in the aging of the reproductive axis in women relative to the rat model. Whereas the hypothalamus is considered an important site of deficit for the age-associated reproductive decline in rats, the ovary has long been considered the primary site of the deficit leading to menopause. Clearly the depletion of the functional ovarian follicular reserve is the immediate cause of the hypoestrogenicity associated with menopause [114]. However, the pattern of follicle loss with age in women is provocative. There is evidence of an accelerated rate of follicular depletion beginning at approximately age 37 [11, 115], more than a decade before the average age of menopause.
Recent studies have revealed an altered gonadotropin profile in premenopausal women prior to detectable disturbances in menstrual cyclicity. Most universally observed are elevated FSH levels [114]. Some studies have provided evidence of altered parameters of LH release consistent with a slowing of LHRH pulse generation in premenopausal women [116] and a further slowing of LHRH pulse generation with advancing age [117]. In contrast to the hypoestrogenicity of menopause, the perimenopausal period is associated with intermittent elevated levels of estradiol and decreased levels of progesterone [114, 118], due primarily to an increased number of developing follicles in the ovaries and a decline in ovulatory cycles [114]. The currently emerging hormonal profile of the perimenopausal period resembles that described in female rats prior to the loss of estrous cyclicity including the increased estradiol:progesterone ratio characteristic of aging female rodents [1, 10] and the decrease in LHRH/LH pulse frequency [75, 82]. Although not previously discussed, increased FSH levels have also been reported in middle-aged cycling rats [119]. Therefore, although the cessation of menstrual cycles is associated with hypoestrogenicity and the cessation of estrous cycles in many rat strains is marked by constant moderate levels of circulating estradiol, the period preceding the cessation of regular estrous and/or menstrual cycles may have more similarities than previously thought.
Considerable interest has focused on the elevated FSH levels that have been hypothesized to hasten the depletion of the follicular reserve. Speculation about the increase in FSH levels in the presence of elevated estradiol levels has centered on a decline in inhibin B production by the ovary [114, 118, 120, 121]. Interestingly, increased FSH levels in rats were also associated with a decrease in inhibin levels [119]. It should be noted that the decrease in LHRH pulse generation inferred from LH measurements in premenopausal women [116] could potentially influence the ratio of circulating gonadotropin levels. As mentioned, studies in rats have revealed that slower LHRH pulse frequency favors FSH release over LH release, and there is evidence that a similar relationship may exist in humans and primates [56]. Therefore it seems plausible that altered parameters of LHRH pulse generation might contribute to increased FSH levels and to the increase in anovulatory menstrual cycles. Alternatively, increased estradiol levels during the perimenopausal period could alter hypothalamic sensitivity to the positive feedback effects of estradiol as described in rodent models [1, 4, 5]. This change could alter LHRH pulse generator activity and contribute to an increase in the number of anovulatory cycles. The possibility that hypothalamic alterations play a role in the events that lead to menopause has received some attention in recent studies of the perimenopausal period [114, 116, 118]. It is a topic that warrants further consideration if we are to understand more fully the complex interactions involved in the regulation of the reproductive axis and the age-related reproductive decline.
|
FOOTNOTES
|
|---|
First decision: 14 February 2000.
1 Studies in the author's laboratory were supported by NIH grants AG 14974 and HD 19174. 
2 Correspondence: Beverly S. Rubin, Department of Anatomy and Cellular Biology, Tufts Medical School, 136 Harrison Avenue, Boston, MA 02111. FAX: 617 636 6536; brubin{at}opal.tufts.edu
Accepted: April 4, 2000.
Received: January 13, 2000.
|
REFERENCES
|
|---|
-
vom Saal FS, Finch CE, Nelson JF. Natural history and mechanisms of reproductive aging in humans, laboratory rodents, and other selected vertebrates. In: Knobil E, Neill JD (eds.), The Physiology of Reproduction. New York: Raven Press; 1994: 1213–1314
-
Lu JKH, Anzalone CR, LaPolt PS. Relation of neuroendocrine function to reproductive decline during aging in the female rat. Neurobiol Aging 1994; 15:541–544[CrossRef][Medline]
-
Wise PM. Neuroendocrine ageing: its impact on the reproductive system of the female rat. J Reprod Fertil Suppl 1993; 46:35–46[Medline]
-
Meites J, Lu JKH. Reproductive ageing and neuroendocrine function. In: Charlton HM (ed.), Oxford Reviews of Reproductive Biology. Oxford, New York, Tokyo: Oxford University Press; 1994: 215–247
-
Lu JKH. Changes in ovarian function and gonadotropin and prolactin secretion in aging female rats. In: Meites J (ed.), Neuroendocrinology of Aging. New York: Plenum Press; 1983: 103–122
-
Nass TE, LaPolt PS, Judd HL, Lu JKH. Alterations in ovarian steroid and gonadotrophin secretion preceding the cessation of regular oestrus cycles in ageing. J Endocrinol 1984; 100:43–50[Abstract/Free Full Text]
-
Wise PM. Alterations in proestrous LH, FSH, and prolactin surges in middle-aged rats. Proc Soc Exp Biol Med 1982; 169:348–354[CrossRef][Medline]
-
Cooper RL, Conn PM, Walker RF. Characterization of the LH surge in middle-aged female rats. Biol Reprod 1980; 23:611–615[Abstract]
-
Gray GD, Tennent B, Smith ER, Davidson JM. Luteinizing hormone regulation and sexual behavior in middle-aged female rats. Endocrinology 1980; 107:187–194[Abstract/Free Full Text]
-
LaPolt PS, Matt DW, Lu JKH. Progesterone implants delay age-related declines in regular estrous cyclicity and the ovarian follicular reserve in Long-Evans rats. Biol Reprod 1998; 59:197–201[Abstract/Free Full Text]
-
Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 1992; 7:1342–1346[Abstract/Free Full Text]
-
Mandl AM, Shelton M. A quantitative study of oocytes in young and old nulliparous laboratory rats. J Endocrinol 1959; 18:444–450
-
Sopelak VM, Butcher RL. Contribution of the ovary versus the hypothalamus-pituitary to termination of estrous cycles in aging rats using ovarian transplants. Biol Reprod 1982; 27:29–37[CrossRef][Medline]
-
Nelson JF, Bergman MD, Karelus K, Felicio LS. Aging of the hypothalamo-pituitary-ovarian axis: hormonal influences and cellular mechanisms. J Steroid Biochem 1987; 27:699–705[CrossRef][Medline]
-
Kirkwood TBL. Ovarian ageing and the general biology of senescence. Maturitas 1998; 30:105–111[CrossRef][Medline]
-
Crawford KA, Hirshfield AN, De Paolo LV. Correlation of age-associated increases in follicle stimulating hormone secretion with decreases in antral follicles: failure of progesterone-induced acyclicity to prevent these changes. Mech Ageing Dev 1992; 64:111–122[CrossRef][Medline]
-
Lerner SP, Meredith S, Thayne WV, Butcher RL. Age-related alterations in follicular development and hormonal profiles in rats with 4-day estrous cycles. Biol Reprod 1990; 42:633–638[Abstract]
-
Brito AN, Sayles TE, Krieg RJ Jr, Matt DW. Relation of attenuated proestrous luteinizing hormone surges in middle-aged female rats to in vitro pituitary gonadotropin-releasing hormone responsiveness. Eur J Endocrinol 1994; 130:540–544[Abstract/Free Full Text]
-
Krieg RJ Jr, Brito AN, Sayles TE, Matt DW. Luteinizing hormone secretion by dispersed anterior pituitary gland cells from middle-aged rats. Neuroendocrinology 1995; 61:318–325[Medline]
-
Hogg BB, Matt DW, Sayles TE. Attenuated proestrous luteinizing hormone surges in middle-aged rats are associated with decreased pituitary luteinizing hormone-beta messenger ribonucleic acid expression. Am J Obstet Gynecol 1992; 167:303–307[Medline]
-
Matt DW, Sayles TE, Jih MH, Kauma SW, Lu JKH. Alterations in the postovariectomy increases in gonadotropin secretion in middle-aged persistent-estrous rats: correlation with pituitary gonadotropin subunit gene expression. Neuroendocrinology 1993; 57:351–358[Medline]
-
Jih MH, Wu TCJ. Altered regulation of pituitary luteinizing hormone secretion by GnRH and inhibin in the aged persistent-estrous female rat. Mech Ageing Dev 1995; 84:15–27[CrossRef][Medline]
-
Collins TJ, Parkening TA. Exposure to estradiol impairs luteinizing hormone function during aging. Mech Ageing Dev 1991; 58:207–220[CrossRef][Medline]
-
Faddy MJ, Gosden RG. A model conforming the decline in follicle numbers to the age of menopause in women. Hum Reprod 1996; 11:1484–1486[Abstract/Free Full Text]
-
Peng M-T, Huang H. Aging of hypothalamic-pituitary-ovarian function in the rat. Fertil Steril 1972; 23:535–542[Medline]
-
Aschheim P. Relation of neuroendocrine system to reproductive decline in female rats. In: Meites J (ed.), Neuroendocrinology of Aging. New York: Plenum Press; 1983: 73–101
-
Felicio LS, Nelson JF, Finch CE. Prolongation and cessation of estrous cycles in aging C57BL/6J mice are differentially regulated events. Biol Reprod 1986; 34:849–858[Abstract]
-
Clemens JA, Amenomori Y, Jenkins T, Meites J. Effects of hypothalamic stimulation, hormones, and drugs on ovarian function in old female rats. Proc Soc Exp Biol Med 1969; 132:561–563[CrossRef][Medline]
-
Quadri SK, Kledzik GS, Meites J. Reinitiation of estrous cycles in old constant estrous rats by central acting drugs. Neuroendocrinology 1973; 11:248–255[Medline]
-
Kalra SP, Horvath T, Naftolin F, Xu B, Pu SY, Kalra PS. The interactive language of the hypothalamus for the gonadotropin releasing hormone (GNRH) system. J Neuroendocrinol 1997; 9:569–576[CrossRef][Medline]
-
Terasawa E. Cellular mechanism of pulsatile LHRH release. Gen Comp Endocrinol 1998; 112:283–295[CrossRef][Medline]
-
Mahesh VB, Brann DW. Neuroendocrine mechanisms underlying the control of gonadotropin secretion by steroids. Steroids 1998; 63:252–256[CrossRef][Medline]
-
Mahesh VB, Brann DW. Regulation of the preovulatory gonadotropin surge by endogenous steroids. Steroids 1998; 63:616–629[CrossRef][Medline]
-
Lei ZM, Rao CV. Novel presence of luteinizing hormone/human chorionic gonadotropin (hCG) receptors and the down-regulating action of hCG on gonadotropin-releasing hormone gene expression in immortalized hypothalamic GT1–7 neurons. Mol Endocrinol 1994; 8:1111–1121[Abstract/Free Full Text]
-
Padmanabhan V, Evans NP, Dahl GE, McFadden KL, Mauger DT, Karsch FJ. Evidence for short or ultrashort loop negative feedback of gonadotropin-releasing hormone secretion. Neuroendocrinology 1995; 62:248–258[Medline]
-
DePaolo LV, King RA, Carrillo AJ. In vivo and in vitro examination of an autoregulatory mechanism for luteinizing hormone-releasing hormone. Endocrinology 1987; 120:272–279[Abstract/Free Full Text]
-
Sarkar DK. In vivo secretion of LHRH in ovariectomized rats is regulated by a possible autofeedback mechanism. Neuroendocrinology 1987; 45:510–513[Medline]
-
Kalra SP. Mandatory neuropeptide-steroid signaling for the preovulatory LH-RH discharge. Endocr Rev 1993; 14:507–538[Abstract/Free Full Text]
-
King JC, Tobet SA, Snavely FL, Arimura AA. LHRH immunopositive cells and their projections to the median eminence and organum vasculosum of the lamina terminalis. J Comp Neurol 1982; 209:287–300[CrossRef][Medline]
-
Silverman AJ. The gonadotropin releasing hormone (GnRH) neuronal systems: immunocytochemistry. In: Knobil E, McNeill J (eds.), Physiology of Reproduction. New York: Raven Press; 1988: 1283
-
King JC, Rubin BS. Dynamic changes in LHRH neurovascular terminals with various endocrine conditions in adults. Horm Behav 1994; 28:349–356[CrossRef][Medline]
-
King JC, Rubin BS. GnRH subgroups: a microarchitecture. In: Conn PM, Crowley WF Jr (eds.), Modes of Action of GnRH and GnRH Analogs. New York: Springer Verlag; 1992: 161–178
-
Hiatt ES, Brunetta PG, Seiler GR, Barney SA, Selles WD, Wooledge KH, King JC. Subgroups of luteinizing hormone-releasing hormone perikarya defined by computer analyses in the basal forebrain of intact female rats. Endocrinology 1992; 130:1030–1043[Abstract/Free Full Text]
-
Van der Beek EM, Wiegant VM, Van der Donk HA, Van den Hurk R, Buijs RM. Lesions of the suprachiasmatic nucleus indicate the presence of a direct vasoactive intestinal polypeptide-containing projection to gonadotrophin-releasing hormone neurons in the female rat. J Endocrinol 1993; 5:137–144
-
Van der Beek EM, Horvath TL, Wiegant VM, Van den Hurk R, Buijs RM. Evidence for a direct neuronal pathway from the suprachiasmatic nucleus to the gonadotropin-releasing hormone system: combined tracing and light and electron microscopic immunocytochemical studies. J Comp Neurol 1997; 384:569–579[CrossRef][Medline]
-
Lee W-S, Smith MS, Hoffman GE. Luteinizing hormone-releasing hormone neurons express Fos protein during the proestrous surge of luteinizing hormone. Proc Natl Acad Sci U S A 1990; 87:5163–5167[Abstract/Free Full Text]
-
Lee W-S, Abbud R, Smith MS, Hoffman GE. LHRH neurons express cJun protein during the proestrous surge of luteinizing hormone. Endocrinology 1992; 130:3101–3103[Abstract/Free Full Text]
-
Hoffman GE, Lee W-S, Attardi B, Yann V, Fitzsimmons MD. Luteinizing hormone-releasing hormone neurons express c-fos antigen after steroid activation. Endocrinology 1990; 126:1736–1741[Abstract/Free Full Text]
-
Marks DL, Smith MS, Vrontakis M, Clifton DK, Steiner RA. Regulation of galanin gene expression in gonadotropin-releasing hormone neurons during the estrous cycle of the rat. Endocrinology 1993; 132:1836–1844[Abstract/Free Full Text]
-
Finn PD, Clifton DK, Steiner RA. The regulation of galanin gene expression in gonadotropin-releasing hormone neurons. Mol Cell Endocrinol 1998; 140:137–142[CrossRef][Medline]
-
Merchenthaler I, Lopez FJ, Negro-Vilar A. Colocalization of galanin and luteinizing hormone-releasing hormone in a subset of preoptic hypothalamic neurons: anatomical and functional correlates. Proc Natl Acad Sci U S A 1990; 87:6326–6330[Abstract/Free Full Text]
-
Gore AC, Wu TJ, Rosenberg JJ, Roberts JL. Gonadotropin-releasing hormone and NMDA receptor gene expression and colocalization change during puberty in female rats. J Neurosci 1996; 16:5281–5289[Abstract/Free Full Text]
-
Porkka-Heiskanen T, Urban JH, Turek FW, Levine JE. Gene expression in a subpopulation of luteinizing hormone-releasing hormone (LHRH) neurons prior to the preovulatory gonadotropin surge. J Neurosci 1994; 14:5548–5558[Abstract]
-
Petersen SL, McCrone S, Keller M, Shores S. Effects of estrogen and progesterone on luteinizing hormone-releasing hormone messenger ribonucleic acid levels: consideration of temporal and neuroanatomical variables. Endocrinology 1995; 136:3604–3610[Abstract]
-
Maurer JA, Wray S. Luteinizing hormone-releasing hormone quantified in tissues and slice explant cultures of postnatal rat hypothalami. Endocrinology 1999; 140:791–799[Abstract/Free Full Text]
-
Marshall JC, Dalkin AC, Haisenleder DJ. Regulation of gonadotropin gene expression by gonadotropin releasing hormone. In: Crowley WFJ, Conn PM (eds.), Modes of Action of GnRH and GnRH Analogs. New York: Springer-Verlag; 1992: 55–68
-
Haisenleder DJ, Dalkin AC, Ortolano GA, Marshall JC, Shupnik MA. A pulsatile gonadotropin-releasing hormone stimulus is required to increase transcription of the gonadotropin subunit genes: evidence for differential regulation of transcription by pulse frequency in vivo. Endocrinology 1991; 128:509–517[Abstract/Free Full Text]
-
Katt JA, Duncan L, Herborn L, Barkian A, Marshall JC. The frequency of gonadotropin-releasing hormone stimulation determines the number of pituitary gonadotropin-releasing hormone receptors. Endocrinology 1985; 116:2113–2115[Abstract/Free Full Text]
-
Yasin M, Dalkin AC, Haisenleder DJ, Kerrigan JR, Marshall JC. Gonadotropin-releasing hormone (GnRH) pulse pattern regulates GnRH receptor gene expression: augmentation by estradiol. Endocrinology 1995; 136:1559–1564[Abstract]
-
Knobil E. The electrophysiology of the GnRH pulse generator in the rhesus monkey. J Steroid Biochem 1989; 33:669–671[CrossRef][Medline]
-
O'Byrne KT, Knobil E. Electrophysiological approaches to gonadotrophin releasing hormone pulse generator activity in the rhesus monkey. Hum Reprod 1993; 8(suppl 2):37–40
-
Stojilkovic SS, Krsmanovic LZ, Spergel DJ, Catt KJ. Gonadotropin-releasing hormone neurons: intrinsic pulsatility and receptor-mediated regulation. Trends Endocrinol Metab 1994; 5:201–209
-
Wetsel WC, Valença MM, Merchenthaler I, Liposits Z, López FJ, Weiner RI, Mellon PL, Negro-Vilar A. Intrinsic pulsatile secretory activity of immortalized luteinizing hormone-releasing hormone-secreting neurons. Proc Natl Acad Sci U S A 1992; 89:4149–4153[Abstract/Free Full Text]
-
Krsmanovic LZ, Martinez-Fuentes AJ, Arora KK, Mores N, Navarro CE, Chen HC, Stojilkovic SS, Catt KJ. Autocrine regulation of gonadotropin-releasing hormone secretion in cultured hypothalamic neurons. Endocrinology 1999; 140:1423–1431[Abstract/Free Full Text]
-
Woller M, Nichols E, Herdendorf T, Tutton D. Release of luteinizing hormone-releasing hormone from enzymatically dispersed rat hypothalamic explants is pulsatile. Biol Reprod 1998; 59:587–590[Abstract/Free Full Text]
-
Terasawa E, Quanbeck CD, Schulz CA, Burich AJ, Luchansky LL, Claude P. A primary cell culture system of luteinizing hormone releasing hormone neurons derived from embryonic olfactory placode in the rhesus monkey. Endocrinology 1993; 133:2379–2390[Abstract/Free Full Text]
-
López FJ, Merchenthaler IJ, Moretto M, Negro-Vilar A. Modulating mechanisms of neuroendocrine cell-activity: the LHRH pulse generator. Cell Mol Neurobiol 1998; 18:125–146
-
Maurer JA, Wray S. Luteinizing hormone-releasing hormone (LHRH) neurons maintained in hypothalamic slice explant cultures exhibit a rapid LHRH mRNA turnover rate. J Neurosci 1997; 17:9481–9491[Abstract/Free Full Text]
-
Yeo TT, Gore AC, Jakubowski M, Dong KW, Blum M, Roberts JL. Characterization of gonadotropin-releasing hormone gene transcripts in a mouse hypothalamic neuronal GT1 cell line. Brain Res Mol Brain Res 1996; 42:255–262[Medline]
-
Jakubowski M, Roberts JL. Processing of gonadotropin-releasing hormone gene transcripts in the rat brain. J Biol Chem 1994; 269:4078–4083[Abstract/Free Full Text]
-
Gore AC, Roberts JL. Regulation of gonadotropin-releasing hormone gene expression in the rat during the luteinizing hormone surge. Endocrinology 1995; 136:889–896[Abstract]
-
Petersen SL, Gardner E, Adelman J, McCrone S. Examination of steroid-induced changes in LHRH gene transcription using 33P- and 35S-labeled probes specific for intron 2. Endocrinology 1996; 137:234–239[Abstract]
-
Lloyd JM, Hoffman GE, Wise PM. Decline in immediate early gene expression in gonadotropin-releasing hormone neurons during proestrus in regularly cycling, middle-aged rats. Endocrinology 1994; 134:1800–1805[Abstract/Free Full Text]
-
Wise PM. Alterations in the proestrous pattern of median eminence LHRH, serum LH, FSH, estradiol and progesterone concentrations in middle-aged rats. Life Sci 1982; 31:165–173[CrossRef][Medline]
-
Rubin BS, Bridges RS. Alterations in luteinizing hormone-releasing hormone release from the mediobasal hypothalamus of ovariectomized, steroid-primed middle-aged rats as measured by push-pull perfusion. Neuroendocrinology 1989; 49:225–232[Medline]
-
Rubin BS, King JC. The number and distribution of detectable luteinizing hormone (LH)-releasing hormone cell bodies changes in association with the preovulatory LH surge in the brains of young but not middle-aged female rats. Endocrinology 1994; 134:467–474[Abstract/Free Full Text]
-
Rubin BS, Lee CE, King JC. A reduced proportion of luteinizing hormone (LH)-releasing hormone neurons express Fos protein during the preovulatory or steroid-induced LH surge in middle-aged rats. Biol Reprod 1994; 51:1264–1272[Abstract]
-
Rubin BS, Mitchell S, Lee CE, King JC. Reconstructions of populations of luteinizing hormone releasing hormone neurons in young and middle-aged rats reveal progressive increases in subgroups expressing Fos protein on proestrus and age-related deficits. Endocrinology 1995; 136:3823–3830[Abstract]
-
Rubin BS, Lee CE, Ohtomo M, King JC. Luteinizing hormone-releasing hormone gene expression differs in young and middle-aged females on the day of a steroid-induced LH surge. Brain Res 1998; 770:267–276
-
Rubin BS, King JC, Bridges RS. Immunoreactive forms of luteinizing hormone-releasing hormone in the brains of aging rats exhibiting persistent vaginal estrus. Biol Reprod 1984; 31:343–351[Abstract]
-
Levine JE, Ramirez VD. In vivo release of luteinizing hormone-releasing hormone estimated with push pull cannulae from the mediobasal hypothalamus. Endocrinology 1980; 107:1782–1790[Abstract/Free Full Text]
-
Scarbrough K, Wise PM. Age-related changes in pulsatile luteinizing hormone release precede the transition to estrous acyclicity and depend upon estrous cycle history. Endocrinology 1990; 126:884–890[Abstract/Free Full Text]
-
Rubin BS, Jimenez-Liñan M. LHRH receptor mRNA levels and gonadotropin subunit mRNA levels are reduced in the pituitaries of middle-aged rats on the dayof a steroid induced LH surge. Soc Neurosci 1999; 25:1960 (abstract)
-
Marchetti B, Cioni M. Opposite changes of pituitary and ovarian receptors for LHRH in ageing rats: further evidence for a direct neural control of ovarian LHRH receptor activity. Neuroendocrinology 1988; 48:242–251[Medline]
-
Smith WA, Cooper RL, Conn PM. Altered pituitary responsiveness to gonadotropin-releasing hormone in middle aged rats with 4 day estrous cycles. Endocrinology 1982; 111:1843[Abstract/Free Full Text]
-
Rubin BS, King JC. A relative depletion of luteinizing hormone-releasing hormone was observed in the median eminence of young but not middle-aged rats on the evening of proestrus. Neuroendocrinology 1995; 62:259–269[CrossRef][Medline]
-
Park OK, Gugneja S, Mayo KE. GnRH gene expression during the rat estrous cycle: effects of pentobarbital and ovarian steroids. Endocrinology 1990; 127:365–372[Abstract/Free Full Text]
-
Zoeller RT, Young WS. Changes in cellular levels of mRNA encoding GnRH in the anterior hypothalamus of female rats during the estrous cycle. Endocrinology 1988; 123:1688–1699[Abstract/Free Full Text]
-
Gruenewald DA, Matsumoto AM. Age-related decreases in serum gonadotropin levels and gonadotropin-releasing hormone gene expression in the medial preoptic area of the male rat are dependent upon testicular feedback. Endocrinology 1991; 129:2442–2450[Abstract/Free Full Text]
-
Gruenewald DA, Naai MA, Marck BT, Matsumoto AM. Age-related decrease in hypothalamic gonadotropin-releasing hormone (GnRH) gene expression, but not pituitary responsiveness to GnRH, in the male brown Norway rat. J Androl 2000; 21:72–84[Abstract]
-
Wise PM. The role of the hypothalamus in aging of the female reproductive system. J Steroid Biochem 1987; 27:713–719[CrossRef][Medline]
-
Sahu A, Kalra SP. Absence of increased neuropeptide Y neuronal activity before and during the luteinizing hormone (LH) surge may underlie the attenuated preovulatory surge in middle-aged rats. Endocrinology 1998; 139:696–702[Abstract/Free Full Text]
-
Sahu A. Absence of increased hypothalamic nitric oxide synthase gene expression during the preovulatory LH surge in middle-aged rats. Neuroreport 1998; 9:4019–4023[Medline]
-
Zuo Z, Mahesh VB, Zamorano PL, Brann DW. Decreased gonadotropin-releasing hormone neurosecretory response to glutamate agonists in middle-aged female rats on proestrus afternoon: a possible role in reproductive aging. Endocrinology 1996; 137:2334–2338[Abstract]
-
Bergman MD, Karelus K, Felicio LS, Nelson JF. Age-related alterations in estrogen receptor dynamics are independent of cycling status in middle-aged C57BL/6J mice. J Steroid Biochem Mol Biol 1991; 38:127–133[CrossRef][Medline]
-
Rubin BS, Fox TO, Bridges RS. Estrogen binding in nuclear and cytosolic extracts from brain and pituitary of middle-aged female rats. Brain Res 1986; 383:60–67[CrossRef][Medline]
-
Wiegand SJ, Terasawa E. Discrete lesions reveal functional heterogeneity of suprachiasmatic structures in regulation of gonadotropin secretion in the female rat. Neuroendocrinology 1982; 34:395–404[CrossRef][Medline]
-
Wiegand SJ, Terasawa E, Bridson WE, Goy RW. Effects of discrete lesions of preoptic and suprachiasmatic structures in the female rat. Alterations in the feedback regulation of gonadotropin secretion. Neuroendocrinology 1980; 31:147–157[Medline]
-
Cai A, Scarbrough K, Hinkle DA, Wise PM. Fetal grafts containing suprachiasmatic nuclei restore the diurnal rhythm of CRH and POMC in aging rats. Am J Physiol 1997; 273:R1764–R1770
-
Wise PM, Kashon ML, Krajnak KM, Rosewell KL, Cai A, Scarbrough K, Harney JP, McShane TM, Lloyd JM, Weiland NG. Aging of the female reproductive system: a window into brain aging. In: Conn PM (ed.), Recent Progress in Hormone Research. New York: Academic Press; 1997: 279–305
-
Cai A, Lehman MN, Lloyd JM, Wise PM. Transplantation of fetal suprchiasmatic nuclei into middle-aged rats restores diurnal Fos expression in host. Am J Physiol 1997; 272:R422–R428
-
Van der Beek EM, Van Oudheusden HJC, Buijs RM, Van der Donk HA, Van den Hurk R, Wiegant VM. Preferential induction of c-fos immunoreactivity in vasoactive intestinal polypeptide-innervated gonadotropin-releasing hormone neurons during a steroid-induced luteinizing hormone surge in the female rat. Endocrinology 1994; 134:2636–2644[Abstract/Free Full Text]
-
Harney JP, Scarbrough K, Rosewell KL, Wise PM. In vivo antisense antagonism of vasoactive intestinal peptide in the suprachiasmatic nuclei causes aging-like changes in the estradiol-induced luteinizing hormone and prolactin surges. Endocrinology 1996; 137:3696–3701[Abstract]
-
Krajnak K, Kashon ML, Rosewell KL, Wise PM. Aging alters the rhythmic expression of vasoactive intestinal polypeptide mRNA but not arginine vasopressin mRNA in the suprachiasmatic nuclei of female rats. J Neurosci 1998; 18:4767–4774[Abstract/Free Full Text]
-
Bronson FH. Effect of food manipulation on the GnRH-LH-estradiol axis of young female rats. Am J Physiol 1988; 254:R616–621
-
Schneider JE, Goldman MD, Leo NA, Rosen ME. Central vs. peripheral metabolic control of estrous cycles in Syrian hamsters. II. Glucoprivation. Am J Physiol 1997; 272:R406–412
-
Wade GN, Schneider JE, Friedman MI. Insulin-induced anestrus in Syrian hamsters. Am J Physiol 1991; 260:R148–152
-
Nagatani S, Bucholtz DC, Murahashi K, Estacio MAC, Tsukamura H, Foster DL, Maeda KI. Reduction of glucose availability suppresses pulsatile luteinizing hormone release in female and male rats. Endocrinology 1996; 137:1166–1170[Abstract]
-
Murahashi K, Bucholtz DC, Nagatani S, Tsukahara S, Tsukamura H, Foster DL, Maeda KI. Suppression of luteinizing hormone pulses by restriction of glucose availability is mediated by sensors in the brain stem. Endocrinology 1996; 137:1171–1176[Abstract]
-
Bronson FH. Food-restricted, prepubertal, female rats: rapid recovery of luteinizing hormone pulsing with excess food, and full recovery of pubertal development with gonadotropin-releasing hormone. Endocrinology 1986; 118:2483–2487[Abstract/Free Full Text]
-
Briski KP, Sylvester PW. Role of endogenous opiates in glucoprivic inhibition of the luteinizing hormone surge and Fos expression by preoptic gonadotropin-releasing hormone neurones in ovariectomized steroid-primed female rats. J Neuroendocrinol 1998; 10:769–776[CrossRef][Medline]
-
Miller MM, Billiar RB, Nelson JF. The loss of LH-RH neurons in the rostral forebrain of old female C57Bl/6J mice. Neurobiol Aging 1990; 11:217–221[CrossRef][Medline]
-
Funabashi T, Kimura F. The number of luteinizing hormone-releasing hormone immunoreactive neurons is significantly decreased in the forebrain of old-aged female rats. Neurosci Lett 1995; 189:85–88[CrossRef][Medline]
-
Prior JC. Perimenopause: the complex endocrinology of the menopausal transition. Endocr Rev 1998; 19:397–428[Abstract/Free Full Text]
-
Faddy MJ, Gosden RG. A mathematical model of follicle dynamics in the human ovary. Hum Reprod 1995; 10:770–775[Abstract/Free Full Text]
-
Matt DW, Kauma SW, Pincus SM, Veldhuis JD, Evans WS. Characteristics of luteinizing hormone secretion in younger versus older premenopausal women. Am J Obstet Gynecol 1998; 178:504–510[CrossRef][Medline]
-
Rossmanith WG, Scherbaum WA, Lauritzen C. Gonadotropin secretion during aging in postmenopausal women. Neuroendocrinology 1991; 54:211–218[Medline]
-
Santoro N, Brown JR, Adel T, Skurnick JH. Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Enodocrinol Metab 1996; 81:1495–1501[Abstract]
-
DePaolo L. Age-associated increases in serum follicle-stimulating hormone levels on estrus are accompanied by a reduction in the ovarian secretion of inhibin. Exp Aging Res 1987; 13:3–7[Medline]
-
Soules MR, Battaglia DE, Klein NA. Inhibin and reproductive aging in women. Maturitas 1998; 30:193–204[CrossRef][Medline]
-
Burger HG. The endocrinology of the menopause. J Steroid Biochem Mol Biol 1999; 69:31–35[CrossRef][Medline]
This article has been cited by other articles:
|
|
|
|
 
W. P. Williams III, E. M. Gibson, C. Wang, S. Tjho, N. Khattar, G. E. Bentley, K. Tsutsui, and L. J. Kriegsfeld
Proximate mechanisms driving circadian control of neuroendocrine function: lessons from the young and old
Integr. Comp. Biol.,
June 14, 2009;
(2009)
icp041v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. S. Neal-Perry, G. D. Zeevalk, J. Shu, and A. M. Etgen
Restoration of the Luteinizing Hormone Surge in Middle-Aged Female Rats by Altering the Balance of GABA and Glutamate Transmission in the Medial Preoptic Area
Biol Reprod,
November 1, 2008;
79(5):
878 - 888.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Wang, M. Garro, H. A. Dantzler, J. A. Taylor, D. D. Kline, and M. C. Kuehl-Kovarik
Age Affects Spontaneous Activity and Depolarizing Afterpotentials in Isolated Gonadotropin-Releasing Hormone Neurons
Endocrinology,
October 1, 2008;
149(10):
4938 - 4947.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Zheng, M. Jimenez-Linan, B. S. Rubin, and L. M. Halvorson
Anterior Pituitary Gene Expression with Reproductive Aging in the Female Rat
Biol Reprod,
June 1, 2007;
76(6):
1091 - 1102.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Shi, K. E. Valdez, A. Y. Ting, A. Franczak, S. L. Gum, and B. K. Petroff
Ovarian Endocrine Disruption Underlies Premature Reproductive Senescence Following Environmentally Relevant Chronic Exposure to the Aryl Hydrocarbon Receptor Agonist 2,3,7,8-Tetrachlorodibenzo-p-Dioxin
Biol Reprod,
February 1, 2007;
76(2):
198 - 202.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Franczak, A. Nynca, K. E. Valdez, K. M. Mizinga, and B. K. Petroff
Effects of Acute and Chronic Exposure to the Aryl Hydrocarbon Receptor Agonist 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on the Transition to Reproductive Senescence in Female Sprague-Dawley Rats
Biol Reprod,
January 1, 2006;
74(1):
125 - 130.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Keenan, W. S. Evans, and J. D. Veldhuis
Control of LH secretory-burst frequency and interpulse-interval regularity in women
Am J Physiol Endocrinol Metab,
November 1, 2003;
285(5):
E938 - E948.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. M. Wise, M. J. Smith, D. B. Dubal, M. E. Wilson, S. W. Rau, A. B. Cashion, M. Bottner, and K. L. Rosewell
Neuroendocrine Modulation and Repercussions of Female Reproductive Aging
Recent Prog. Horm. Res.,
January 1, 2002;
57(1):
235 - 256.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. M. Adams, R. A. Shah, W. G. M. Janssen, and J. H. Morrison
Different modes of hippocampal plasticity in response to estrogen in young and aged female rats
PNAS,
June 20, 2001;
(2001)
141215898.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. M. Adams, R. A. Shah, W. G. M. Janssen, and J. H. Morrison
Different modes of hippocampal plasticity in response to estrogen in young and aged female rats
PNAS,
July 3, 2001;
98(14):
8071 - 8076.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
ABSTRACT
REGULAR ESTROUS CYCLES CEASE...
