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*Menopause
Endocrinology Vol. 145, No. 10 4653-4659
Copyright © 2004 by The Endocrine Society

Menopausal Increases in Pulsatile Gonadotropin-Releasing Hormone Release in a Nonhuman Primate (Macaca mulatta)

Andrea C. Gore, Bret M. Windsor-Engnell and Ei Terasawa

Division of Pharmacology and Toxicology, College of Pharmacy, Institute for Neuroscience, and Institute for Cellular and Molecular Biology (A.C.G.), The University of Texas at Austin, Austin, Texas 78712; and Wisconsin National Primate Research Center (B.M.W.-E., E.T.) and Department of Pediatrics (E.T.), University of Wisconsin, Madison, Wisconsin 53715

Address all correspondence and requests for reprints to: Andrea C. Gore, Ph.D., University of Texas at Austin, Division of Pharmacology/Toxicology, Austin, Texas 78712. E-mail: andrea.gore{at}mail.utexas.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Reproductive function in all vertebrates is controlled by the circhoral release of the neuropeptide, GnRH, into the portal capillary system leading to the anterior pituitary. Despite its primary role in sexual maturation and the maintenance of adult reproductive function, changes in the concentrations and pattern of GnRH release have not yet been reported in any primate species during the menopausal transition and postmenopause. Such knowledge is essential for ascertaining both the mechanisms for, and consequences of, the menopausal process. Here we used a push-pull perfusion method to measure and compare the parameters of pulsatile GnRH release in adult rhesus monkeys at 8.4 ± 1.5 yr (young adult females, early follicular phase, n = 6) and 28.8 ± 0.3 yr (aged females, n = 4, of which two monkeys were in the menopausal transition, and two were postmenopausal). Our results demonstrate that: 1) GnRH release is pulsatile in both young and aged monkeys; 2) mean concentrations of GnRH increase during reproductive aging; and 3) GnRH pulse frequency does not differ between aged monkeys and young monkeys in the early follicular phase. We conclude that not only do GnRH neurons have the continued capacity to release GnRH in a pulsatile manner but also they can do so with enhanced GnRH levels in aged primates. To our knowledge, this is the first direct demonstration of elevated pulsatile GnRH concentrations in a primate species during reproductive senescence, a result that may have implications for menopausal symptoms.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE HYPOTHALAMIC GnRH decapeptide is essential for reproductive processes in vertebrates. GnRH plays key roles in the onset and progression of reproductive maturation, regulation of hormonal changes that occur during menstrual and estrous cycles, and mediation of reproductive system responses to seasonal or diurnal cues (1, 2, 3, 4, 5). In primates, GnRH is released at approximately hourly intervals from neuroterminals in the median eminence (6, 7). This pulsatile pattern is obligatory to normal reproductive function because continuous elevations in GnRH release eventually suppress pituitary gonadotropin biosynthesis and release (8).

Despite its clear role in puberty and the maintenance of adult reproductive function in mammals, relatively little is known about whether GnRH release changes during aging and whether this plays a role in reproductive senescence. In addition, the importance of GnRH in reproductive aging may differ among species. Female rodents undergo a transition from regular estrous cycles to irregular cycles to acyclicity, a phenomenon sometimes referred to as estropause, which appears to be largely ovarian independent (9, 10 ; reviewed in Ref.11). Accruing evidence from our laboratory as well as others suggests a role for GnRH neurons in reproductive senescence in female rats (12, 13, 14, 15, 16, 17, 18, 19). However, the possible role of GnRH in reproductive aging in primates is probably more complex than that in rodents. In primates, follicular atresia is likely of far greater importance to reproductive senescence, compared with rodent species (20, 21, 22, 23).

GnRH release in aging primates, including women, is usually inferred indirectly from gonadotropin or gonadotropin-free {alpha}-subunit levels (24, 25, 26). A recent study in female monkeys showed that pulsatile LH release is substantially elevated during aging (24). Studies in aging women have reported that gonadotropin concentrations are elevated in early postmenopause, compared with levels in premenopausal women (27, 28, 29). Nevertheless, the pituitary itself may also undergo age-related changes, including altered sensitivity to GnRH, which may account for altered gonadotropin release during aging. It is therefore important to make direct measurements of pulsatile GnRH release. These experiments cannot be performed in women due to the inaccessibility of GnRH neuroterminals at the base of the brain and an inability to detect GnRH peptide in the peripheral circulation. We have taken advantage of the similarity of the 28-d menstrual cycles of rhesus monkeys and humans (30, 31, 32) to characterize age-related changes in GnRH pulsatile release. Here we directly measured GnRH release in young (premenopausal) and aged (in the menopausal transition or postmenopausal) rhesus monkeys (Macaca mulatta) using a push-pull perfusion technique. Our results provide clear evidence for an age-related elevation in GnRH concentrations.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Female rhesus monkeys (Macaca mulatta) were obtained from the Wisconsin National Primate Research Center, the California National Primate Research Center, or an aged monkey colony maintained at The University of Illinois-Chicago/Rush-Presbyterian Medical Center. All experimentation was performed at the Wisconsin National Primate Research Center, and protocols were approved by the Institutional Animal Care and Use Committee at the University of Wisconsin following guidelines provided in The Guide for the Care and Use of Laboratory Animals. Monkeys were experimentally naïve other than minor, noninvasive procedures before experimentation and had been monitored for at least 1 yr for menstrual cyclicity or the cessation thereof. Four aged (28.8 ± 0.3 yr, range 26.9–30.6 yr) and six young (8.4 ± 1.5 yr, range 4.0–12.7 yr) monkeys were used for studies. Daily monitoring for the appearance of perineal sex skin and menses (33, 34) indicated that two of the aged monkeys were in the menopausal transition (infrequent menstrual cycles with long intervals between cycles throughout the year), and two were postmenopausal (no menstrual cycles for a 2-yr period). This nomenclature for monkeys was adopted from the convention of the STRAW (stages of reproductive aging workshop) panel on menopause in women (35). Aged monkeys were in general good health when experiments were conducted, although they did have some age-related impairments that are typical of very aged monkeys (e.g. kyphosis, missing and worn teeth, arthritis). All of the young monkeys had regular monthly menstrual cycles as determined by daily observation of changes in perineal sex skin color and the appearance of menses, before and during experimentation.

Push-pull perfusates were collected in young animals during the early follicular phase of the menstrual cycle (within 7 d of the first appearance of menses). Two of the aged monkeys were postmenopausal and did not have any menstruation during the year before experimentation or throughout the course of the study. Two other aged monkeys experienced irregular menstruation: one (Rh 7) had irregular menstruation at 3.5- to 4.5-month intervals over a 1.5-yr period. Push-pull perfusion experiments on Rh 7 were conducted twice, once at 3.7 months and once at 7 d after the last menstruation, the latter time comparable with that used for experimentation in young monkeys. The other perimenopausal monkey, Rh 10, had no menstruation for the year before experimentation and exhibited menstruation at 10- to 13-month intervals during the course of experimentation. The push-pull perfusion experiment on Rh 10 was conducted 3 months after the last menstrual period. Due to the rigor of a serial blood drawing procedure, it was not possible to measure pulsatile LH release in serum together with pulsatile GnRH release in push-pull perfusates in very aged monkeys. Nevertheless, both young and aged monkeys were subjected to weekly blood sampling (3 cc) from the femoral vein for subsequent measurements of serum hormone concentrations; results of serum progesterone assays confirmed early follicular phase status in the cycling monkeys. Animals were housed two per cage in a room with controlled lighting (12-h light, 12-h dark, lights on 0600 h) and temperature (22 C). Monkeys were fed a standard diet of Purina monkey chow daily, supplemented with fresh fruit several times weekly. Water was available ad libitum. At the completion of this project, all aged females were deeply anesthetized and humanely killed for necropsy.

Implantation of cranial pedestal
Monkeys (under halothane anesthesia) were implanted with a cranial pedestal as described previously in detail (34, 36, 37). Animals were allowed to recover for at least 1 month before experimentation. During this time, monkeys were well adapted to the primate chair, the experimental environment, and the investigator (34, 36).

Implantation of a push-pull cannula
Monkeys were anesthetized with ketamine (10 mg/kg body weight) and xylazine (2 mg) and placed on a stereotaxic apparatus. An outer cannula (20 gauge) containing a stylet (27 gauge) was inserted into the stalk-median eminence, the site of GnRH neuroterminals (36), using a hydraulic microdrive unit (M095-B; Narishige, Tokyo, Japan). The cannula placement was compared with ventriculograms taken during the pedestal implantation surgery to ensure that the tip of the cannula was within 1 mm of the infundibular recess and 0.8–1.6 mm ventral to the infundibular recess (34, 36). After cannula insertion, the monkey was placed in a primate chair and allowed to recover for 1 d before experimentation. During this time, as well as during experimentation, monkeys were placed in proximity to a companion monkey; given constant access to food and water; and were provided frequent fruit, cereal, raisins, and other snacks.

Experimental design
On the day of experimentation, the inner stylet was removed from the cannula and replaced with an inner cannula (29 gauge) through which modified Krebs-Ringer phosphate buffer solution (38) was infused at 23 µl/min using a peristaltic pump (Minipulse3; Gilson Medical Electronics, Middleton, WI). Perfusate was collected continuously in 10-min fractions on ice from the outer cannula using an identically calibrated pump for 9–12 h (starting at 1000 h) from the stalk-median eminence, in which GnRH neuroterminals are concentrated (36). One hundred fifty microliters of sample were aliquoted for subsequent measurement of GnRH levels by RIA. Samples were frozen and stored at –70 C.

RIAs
GnRH in perfusate samples was measured by RIA (36, 39) using antiserum R1245 (kindly provided by Dr. T. Nett) (40). Synthetic GnRH (Richelieu Laboratory, Montréal, Canada) was used for the radiolabeled antigen and the reference standard. The antigen-antibody complex was precipitated with a sheep antirabbit {gamma}-globulin. Sensitivity of the assay was 0.1 pg/tube. Intraassay coefficient of variation was 8.1%, and interassay coefficient of variation was 11.3%.

Serum hormone concentrations were measured by RIA as described previously (24, 41, 42). All samples were assayed within a single assay on duplicate samples. The intraassay coefficients of variation for the LH, FSH, estradiol, and progesterone assays were 3.7, 3.2, 2.4, and 1.8%, respectively. Assay sensitivities of LH, FSH, estradiol, and progesterone were 0.2 ng/tube, 3.0 pg/tube, 2 pg/tube, and 5 pg/tube at 90% binding, respectively. The LH standard was WFP-rh-LH-RP1, and the FSH standard was recombinant monkey FSH-RP1.

Statistical analysis
Pulses of GnRH were determined by the PULSAR algorithm, using parameters identical with those described previously (43, 44). In brief, cutoff criteria G1, G2, G3, G4, and G5 were 3.8, 2.6, 1.9, 1.5, and 1.2, respectively, for pulse determination. Mean GnRH concentration, pulse amplitude, and interpulse interval were taken from the PULSAR reports. Differences between young and old animals were determined using a mixed-model approach for analyzing repeated measures data, following a Box-Cox transformation before analysis, as described previously (45). Differences were considered significant at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Measurements of GnRH concentrations in perfusate samples of six young (8.4 ± 1.5 yr) and four aged (28.8 ± 0.3 yr) rhesus monkeys by RIA showed that GnRH release was pulsatile in all of the animals in this study. Figure 1Go shows pulsatile GnRH release in three representative young monkeys. Figure 2Go shows pulsatile GnRH release in three representative aged monkeys. In addition, three of four of the aged monkeys exhibited extremely large pulses (>30 pg/ml) of GnRH (Fig. 2Go) that were not observed in the young monkeys (Fig. 1Go).



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  		FIG. 1. Representative examples of pulsatile GnRH release measured by push-pull perfusion in young rhesus monkeys, all with regular monthly menstrual cycles. Experiments were conducted during the early follicular phase in all monkeys. Arrows indicate significant pulses detected by the PULSAR program. Note differences in the y-axis between individuals.

 


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  		FIG. 2. Representative examples of pulsatile GnRH release measured by push-pull perfusion in aged rhesus monkeys. Monkeys Rh 9 and Rh 8 were postmenopausal (no menstrual cyclicity for 2+ yr), and monkey Rh 7 was in the menopausal transition. Arrows indicate significant pulses detected by the PULSAR program. Note differences in the y-axis between individuals and shifts in scale in two animals (Rh 7 and Rh 8).

 
The parameters of GnRH release were analyzed using the PULSAR algorithm (43, 46). As shown in Fig. 3AGo, mean GnRH concentrations were approximately 3.7-fold higher in the aged than the young female monkeys; this is a significant difference between age groups (P < 0.05). Although GnRH pulse amplitude (Fig. 3BGo) tended to be higher in the aged than the young monkeys (approximately 3.5-fold increase), this was not significantly different (P = 0.12) due to the large variability among the individual animals (e.g. see Figs. 1Go and 2Go). Note that individual differences were due to neither the difference in the endocrine status nor the location of the sample collection within the stalk-median eminence. For example, the first monkey (Rh 9) in Fig. 2Go in which relatively low GnRH levels were observed was postmenopausal, the second monkey (Rh 8) with high GnRH levels was also postmenopausal, whereas the third monkey (Rh 7) in Fig. 2Go, also with very high GnRH levels, was in the menopausal transition. In all three animals, perfusate samples were obtained from comparable locations in the stalk-median eminence. GnRH interpulse interval, the time between two consecutive pulses (Fig. 3CGo), did not differ between the young and aged animals and was similar to that previously reported in female rhesus macaques (approximately 48 min) (34, 39).



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  		FIG. 3. PULSAR analysis of GnRH pulse parameters in young (black bar) and aged (gray bar) rhesus monkeys. A, Mean GnRH concentrations. B, GnRH pulse amplitude. C, GnRH interpulse interval. *, P < 0.05, compared with young monkeys. Data shown are mean ± SEM.

 
Concentrations of LH, FSH, estradiol, and progesterone were assessed by RIA in serum samples collected weekly by venipuncture from the same rhesus monkeys that were used for the push-pull perfusion experiments. As shown in Fig. 4Go, FSH concentrations were significantly elevated in aged rhesus monkeys (P < 0.005), and LH levels tended to be elevated (P = 0.06), compared with young premenopausal monkeys. Estradiol concentrations were significantly lower in the aged than the young monkeys (P < 0.005). Progesterone concentrations did not differ between the two age groups. These age-related changes in circulating hormones in rhesus monkeys are similar to those previously reported in aged intact rhesus monkeys (24).



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  		FIG. 4. Serum hormone profiles in young and aged female rhesus monkeys. All hormones were assayed by RIAs. A, LH. B, FSH. C, Estradiol. D, Progesterone. *, P < 0.005, compared with young monkeys. Data shown are mean ± SEM.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study is the first to report direct measurements of GnRH release in any primate species during the menopausal transition. Our results show that GnRH continues to be released in a pulsatile pattern even in very aged rhesus monkeys. In addition, mean GnRH concentrations in female rhesus monkeys were significantly elevated with aging, and we detected extremely large bursts of GnRH release in most of our aged monkeys but not our young monkeys. To our knowledge, these large GnRH pulses have not previously been reported for any other species during aging. The concentrations of GnRH in our aged female rhesus monkeys are as high as or higher than those measured in our laboratory using a similar experimental approach in ovariectomized (OVX) midpubertal or young adult monkeys (34, 46, 47, 48). By contrast, the frequency of GnRH pulses remained constant during reproductive aging and was similar among young (early follicular phase) adult and aged monkeys. This interpulse interval of approximately 50 min was also similar to that of rhesus monkeys at earlier developmental stages beginning at midpuberty through early adulthood (34, 39, 46, 49). Thus, during aging in female rhesus monkeys, there are changes in GnRH concentrations but not GnRH pulse frequency.

A recent study in a similar aged cohort of monkeys demonstrated age-related increases in pulsatile LH release (24), and in the present study, there was a trend (P < 0.06) for LH levels to be higher in aged than young monkeys, although this did not attain significance due to individual variation and the small number of subjects in the aged group. In the previous study (24), mean LH levels and LH pulse amplitude, but not pulse frequency, in aged females were significantly higher than in young females. This result, which is likely applicable to women, would correspond well with and likely be causal to the increased LH, FSH, and gonadotropin-free {alpha}-subunit release, and GnRH gene expression, during the menopausal transition (25, 26, 50, 51).

Reports in women measuring gonadotropin levels or gonadotropin-free {alpha}-subunit as an indirect reflection of GnRH have suggested that GnRH release may increase with aging (25, 26, 50). Rance and Uswandi also reported an elevation in GnRH mRNA levels in postmenopausal, compared with premenopausal, women (51). However, some studies (52, 53) suggest that gonadotropin secretion may not change with aging in women; differences among results may be attributed to the sampling method, the postmenopausal stage of the subjects, the ovarian status, and other technical differences. We believe that our finding of an increase in GnRH concentrations in aged monkeys sheds additional light on the manner in which the aging reproductive axis changes, and our data demonstrate a direct alteration in GnRH output, not just a change in pituitary function or responsiveness to GnRH.

In our aged monkeys, the lower circulating estradiol levels and the subsequent reduction in estradiol-negative feedback probably contribute to the increased GnRH concentrations. Comparisons of circulating hormone data between intact aged monkeys and OVX young adult females illuminate the potential role of decreased estradiol-negative feedback in the elevated GnRH and LH concentrations. Although LH and GnRH levels in aged monkeys (58 ± 22 ng/ml and 7.4 ± 4.0 pg/ml, respectively) are elevated, they are not as consistently high as those previously reported in young OVX female monkeys in other studies done in the laboratory of Terasawa and colleagues (>100 ng/ml and > 10 pg/ml, respectively) (38, 48, 54). This may be due to the higher estrogen concentrations in aged monkeys (37 ± 5 pg/ml) relative to those in OVX adult females (typically 10–20 pg/ml) (38, 48, 55, 56, 57, 58). Whereas caution needs to be used in comparing hormone assays across studies, in general, results are quite consistent. Progesterone probably does not play a role in this negative feedback because its concentrations are similar in the young and aged intact monkeys in our present study (0.44 ± 0.1 and 0.33 ± 0.1 ng/ml, respectively) as well as in OVX monkeys (0.4 ng/ml). Our preliminary data from this and previous (24) studies showing that LH levels in postmenopausal females (n = 4) were higher than those in females (n = 6) at the menopausal transition, corresponding to generally lower estrogen levels in postmenopausal females than those at the transitional stage (Terasawa, E., and A. C. Gore, unpublished data), further support the role of estrogen in aging. It has also been shown that estradiol replacement in female monkeys decreased GnRH release (54), GnRH gene expression (59, 60), and multiunit activity (presumably reflecting the GnRH pulse generator) (61). In humans, estrogen replacement to postmenopausal women decreased LH and FSH concentrations, and older postmenopausal women were more responsive than younger postmenopausal women to these negative effects, demonstrating that the responsiveness to estradiol-negative feedback is maintained or even increased with aging (25, 62). We were able to test effects of estrogen-negative feedback on GnRH release in one of our aged monkeys, and the results suggested that estradiol treatment decreased pulsatile GnRH release (Gore, A. C. and E. Terasawa, unpublished data). However, additional studies are necessary to confirm this preliminary observation.

Age-related changes in the hypothalamus itself may contribute to the elevated GnRH concentrations in the aged monkeys. As seen in our results, GnRH concentrations in ovarian-intact aged female monkeys were as high as or higher than those reported in OVX females at the midpubertal stage, the time when the maximum GnRH ouput occurs, resulting in puberty (48). Although we have not measured GnRH release in OVX aged monkeys and the degree to which hypothalamic aging as opposed to the aging-related reduction in estrogen contributes to the elevation of GnRH release in aged monkeys remains to be identified, there are two examples to support the concept of hypothalamic aging. First, we had observed that reductions in pulsatile GH (24) and decreased GHRH release together with an increase in somatostatin release from the hypothalamus (63) occurred in a group of aged females very similar to those in the present study. It has been reported that the aging-related reduction in GH release in women is due to both hypothalamic changes and estrogen withdrawal at menopause (64). Second, the similarity in time courses of peak occurrences of hot flashes and gonadotropin elevations during the menopausal transition, followed by a diminution with time postmenopause (50), suggests that the aging hypothalamus is responsible for hot flashes and alterations in GnRH release (65). This concept of hypothalamic aging is still only speculative, and the questions still remain as to whether the same set of hypothalamic neurons is responsible for all these aging mechanisms, or which neuronal substrates are involved in the menopausal alteration of the steroidal environment.

The present results also demonstrate differences between macaques and humans in the timing of menopause relative to the maximum lifespan. Although it has been reported that reproductive aging in the macaque family starts as early as 18 yr of age in Macaca fuscata (Japanese macaque) (66), more than 70% of female rhesus monkeys in our colony exhibit regular or irregular menstrual cycles after 25 yr of age. We previously estimated that female rhesus monkeys at 25–30 yr of age are equivalent in reproductive status to 65–90 yr of age in women (24). Despite the relatively later age of menopause in monkeys, the results of the present study support the value of the menopausal, ovarian-intact monkey as a model for reproductive aging in women (67). The variability in levels of circulating hormones in our intact aged monkeys also parallel the natural variability in hormonal changes during aging in women (32).

In conclusion, in the present study, we have provided clear evidence for the longstanding but unproven hypothesis that an increase in pulsatile GnRH release, manifested by robustly elevated GnRH concentrations, occurs during the menopausal transition in a primate. This is likely due in large part to withdrawal of estrogen at menopause, which changes the homeostasis of neuronal network in the hypothalamus, resulting in an increase in GnRH release, hot flashes, and possibly other hypothalamic hormonal changes such as the decrease in GHRH and the increase in somatostatin release that we recently reported (63). The aged monkey model presented in this study can provide direct answers to questions regarding menopausal women’s health.


   Acknowledgments
 
We thank Drs. John H. Morrison and Bruce McEwen for helpful discussions and comments on the manuscript, Dr. David Crews for a critical reading, Dr. W. Y. Wendy Lou for statistical analysis, and Kim L. Keen for assistance with RIAs.


   Footnotes
 
This work was supported by generous funding from The Brookdale Foundation and the National Institutes of Health (PO1 AG16765, to A.C.G., and R01 AG17942, to E.T.). This research was performed at the Wisconsin National Primate Research Center (5P51 RR 000167).

Abbreviation: OVX, Ovariectomized.

Received March 24, 2004.

Accepted for publication June 25, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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