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From the Clinical Research Centers |
Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114
Address correspondence and requests for reprints to: Janet E. Hall, M.D., Reproductive Endocrine Unit, BHX-5, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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-subunit (FAS) and LH as neuroendocrine markers of
endogenous GnRH secretion. All studies were performed in healthy,
euthyroid postmenopausal women (PMW) during daytime hours. The impact
of sampling interval and duration on assessment of pulse frequency in
PMW was first examined in 10 women with a mean age of 61.6 ± 8 yr
(mean ± SD), in whom blood was sampled every 5 min
for 12 h. Each 5-min series was then reduced to simulate a 10-min
series and then a 15-min series for pulse analysis, and the
effect of 8 h compared with 12 h of sampling was
determined. To define the changes in the frequency and amplitude of
pulsatile hormone secretion with aging, 11 younger (45–55 yr) and 11
older (70–80 yr) PMW were then studied over 8 h at a 5-min
sampling interval. In the initial series, the mean interpulse intervals (IPIs) for FAS were 53.8 ± 3.6, 69.2 ± 3.9, and 87.6 ± 7.3 min at sampling intervals of 5, 10, and 15 min, respectively (P < 0.0005). The LH IPI also increased progressively with sampling intervals of 5, 10, and 15 min (54.4 ± 2.5, 70.4 ± 2.3, and 91.1 ± 4.4 min; P < 0.0001). At the 5-min sampling interval, the calculated number of pulses/24 h was not different between a 12-h series compared with an 8-h series for either FAS or LH. In the second series of studies, the older PMW had lower gonadotropin levels (LH, 86.5 ± 8.8 vs. 51.3 ± 7.7 IU/L, P < 0.01; FSH, 171.6 ± 16.9 vs. 108.2 ± 10.5 IU/L, P < 0.005; FAS, 1021.5 ± 147.4 vs. 425.6 ± 89.6 ng/L, P < 0.005, in younger and older PMW, respectively) despite no differences in estrone or estradiol levels. The older PMW also demonstrated a slower FAS pulse frequency compared with their younger counterparts, as reflected in an increased FAS IPI (52.6 ± 3.1 and 70.6 ± 5.9 min; P < 0.002). The difference in IPIs between younger and older PMW was not statistically significant for LH (65.4 ± 5.6 and 71.8 ± 6.6 min for younger and older PMW, respectively). FAS pulse amplitude was decreased in older PMW compared with younger PMW (431.7 ± 66.2 vs. 224.6 ± 81.9 ng/L; P < 0.01), whereas the decrease in LH pulse amplitude with age was of borderline statistical significance (23.2 ± 3.1 vs. 15.9 ± 2.1 IU/L; P = 0.09).
In conclusion: 1) the use of a 5-min sampling interval and measurement of FAS as the primary marker of GnRH pulse generator activity indicate that GnRH pulse frequency in younger PMW is faster than previously reported, but not increased over that seen in the late follicular phase and midcycle surge in women with intact ovarian function; and 2) the marked decrease in FAS pulse frequency with age provides evidence of age-related changes in the hypothalamic component of the reproductive axis that are independent of changes in gonadal function.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The loss of gonadal hormone secretion during the menopause in women
makes it possible to investigate the independent effect of aging on the
hypothalamic and pituitary components of the reproductive system. A
marked increase in serum levels of LH and FSH occurs in postmenopausal
women (PMW) when freed from the negative feedback effects of ovarian
steroidal and nonsteroidal factors (3, 4, 5). However, after menopause,
levels of LH, FSH, and gonadotropin free -subunit (FAS) decline
steadily as a function of age in some (6, 7, 8), but not all (9, 10, 11),
studies. This age-related decline in gonadotropin secretion in PMW may
result from changes in hypothalamic GnRH stimulation, from direct
alterations in the secretory capacity of the gonadotropes, or from
changes in other factors that impact on gonadotropin secretion.
Pulsatile LH has been used as a surrogate marker of GnRH pulse frequency in the human based on its validation in a number of animal species in which peripheral LH pulses were correlated with more direct measures of GnRH secretion (12, 13, 14, 15). In menopausal women, a decrease in LH pulse frequency with age has been found in some studies (8, 11), but was not apparent in others (10, 16). However, the ability of previous studies to provide a reliable estimate of GnRH pulse frequency in the absence of ovarian feedback and to detect changes in that frequency as a result of age may have been hampered by several methodologic considerations. The first is that LH may not be the best marker of fast frequencies of pulsatile GnRH secretion. Increasing evidence would support the concept that in euthyroid subjects the pulsatile component of FAS is also reflective of GnRH secretion (17, 18, 19) despite the dual control of FAS by GnRH and TRH (20). There is now evidence from studies in GnRH-deficient men, that FAS [which has a shorter half-life than the intact hormone (21, 22)], is a more faithful marker of antecedent GnRH stimulation than is LH at the fast GnRH pulse frequencies encountered in PMW (23). The advantage of FAS over LH is likely to be even more profound in PMW than in GnRH-deficient men because plasma clearance of LH is prolonged following menopause, whereas that of FAS remains unchanged (22). A second consideration is that the sampling frequency used in previous studies may not have been optimal. It has been predicted that a sampling frequency of every 5 min is required for detection of pulse frequencies in the circhoral range (24). We have previously demonstrated this to be true in studies of the midcycle surge, another situation in which GnRH pulse generator activity was expected to be rapid (25).
To further address these issues, this study was designed to: 1) examine the impact of blood sampling intervals on the assessment of pulsatile secretion of FAS and LH in PMW; 2) determine the frequency of GnRH pulse generator activity in PMW in the absence of hormonal feedback; and 3) determine the effect of age on GnRH pulse frequency and gonadotropin dynamics.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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All subjects were healthy PMW who had experienced their last menstrual period a minimum of 12 months previously. Subjects had not used hormone replacement for a minimum of 3 months before the study and were not taking other medications, with the exception of 324 mg/day ferrous gluconate administered for a month before the frequent sampling study. Normal TSH, PRL, complete blood count, and electrocardiogram were documented in all subjects. Body mass index (BMI) was 25.5 ± 3.9 kg/m2 (mean ± SD; range, 20.2–34.5). Five subjects had undergone bilateral oophorectomy in the past, whereas the majority had undergone natural menopause. Subjects participated in one of two protocols, both of which were approved by the Subcommittee on Human Studies of the Massachusetts General Hospital, and signed informed consent was obtained from each subject before participation.
Experimental protocol
In the first series of studies, 10 PMW aged 61.6 ± 8 yr (mean ± SD; range, 48–77) were admitted to the Clinical Research Center of the Massachusetts General Hospital for a 12-h period beginning at 0800 h. Blood was sampled every 5 min through an antecubital iv catheter using a blood-sparing technique that has been described previously using isovolumetric fluid replacement (25). In the second series of studies, 11 younger (45–55 yr) and 11 older (70–80 yr) PMW women were admitted for an 8-h period. Based on the results of the initial series, blood was sampled at 5-min intervals beginning at 0800 h. All samples in both series were analyzed for LH and FAS. Serum FSH, estrone (E1), and estradiol (E2) levels were determined in a pool constituted from equal aliquots of serum from each of the frequent samples.
Assays
Serum LH and FSH levels were determined in previously described
RIAs using the Second International Reference Preparation of human
menopausal gonadotropins as the reference standard (26). The
sensitivity of the LH and FSH assays was 0.8 IU/L. FAS concentrations
were determined using a monoclonal antibody RIA, using highly purified
-subunit of human CG obtained from Biomerica, Inc. (Newport Beach,
CA) as the standard. The sensitivity of the FAS assay was 30 ng/L, and
the cross-reactivity of LH in the FAS assay was 0.7%, and likely due
to FAS contamination of the LH standard (27). For LH and FAS
determinations, pools were constituted from the 5-min samples for each
study and run at several volumes in a preliminary assay. These results
were used to adjust the sample volume in the assay so that all points
fell within the linear portion of the assay curve. The intra-assay
coefficients of variation (CV) were determined for each study from the
pool for each subject run at least 10 times throughout the assay. The
overall mean intra-assay CV for all studies were 5.8% and 5.4% for LH
and FAS, respectively. Serum E1 was measured by
RIA, according to manufacturer’s specifications, using a kit from
Diagostics Systems Laboratories, Inc. (Webster TX;
DSL-8700). The limit of detection was 1.2 pg/mL with an intra-assay CV
of 5.6–9.4% and an interassay CV of 6.0–11.1%. Serum
E2 was measured using an automated, random
access, microparticle enzyme immunoassay system (AxSYM; Abbott
Diagnostics, Inc., Chicago, IL). The method was validated and
characterized on-site using specimens from normal subjects obtained
with informed consent. Analytical sensitivity of 10 pg/mL was
determined as the dose equivalent of the 2 SD limits of
replicate determinations of the zero dose calibrator. Within assay
precision was determined using replicate measurements of three quality
control sera containing E2 concentrations
spanning the levels seen in normally cycling women. Within assay CV
ranged from 2.1–4.5%. Between assay precision was determined using
six quality control sera used to monitor assay performance (Trilevel
AxSYM Controls, Abbott Diagnostics, Inc., and Trilevl Ligand Controls,
Chiron Corp. Diagnostics, Walpole, MA) and ranged
from 6.5–9.6%. Assay calibrators, verified by gas chromatography/mass
spectroscopy, were obtained from the manufacturer and used according to
the manufacturer’s specifications. Accuracy was determined on-site by
evaluation of patient specimen linearity and by comparison to the RIA
previously used in this laboratory (28) and Abbott IMx.
Data analysis
Pulses of LH and FAS were identified using Cluster (29). The parameters chosen were a nadir and peak size of 2 x 2 with a t statistic value of 2.0 for both upstroke and downstroke. We have recently shown this algorithm to maximize the detection of true positive pulses and minimize the detection of false positive pulses based on in vivo validation studies (23) and to be equivalent to the modification of the Santen & Bardin program used extensively in this laboratory for detection of LH and FAS pulses in previous studies (19, 25, 30).
To determine the importance of sampling frequency in the identification of LH and FAS pulses, data collected every 5 min from the first series of studies were modified by removing every second and every third data point to simulate samples drawn at 10- and 15-min intervals, respectively. The resulting series were then reanalyzed using the described pulse analysis technique and results compared using ANOVA for repeated measures with post hoc Newman-Keuls testing. The number of pulses detected in the 5-min sampling 12-h series was expressed per 24 h and compared to pulses/24 h derived from the data series truncated at 8 h using paired t tests to determine whether the sampling period could be shortened from 12 h to 8 h without significant loss of information.
In the second series, tests of normality indicated that mean hormone levels were normally distributed, but interpulse interval (IPI) and amplitude data were not; thus, statistical comparisons were performed on log-transformed values. ANOVA was also used to examine the effect of age on mean levels of LH, FSH, and FAS and log LH and FAS IPI and pulse amplitude. Because the overall P value was 0.006, post-hoc Newman-Keuls testing was used to determine age effects for each variable. The effect of age on GnRH pulse frequency was further examined by correlating age with the log of FAS and LH IPI from the 5-min data obtained from both series. Values are expressed as mean ± SEM, unless otherwise indicated, and the median is also presented in instances in which the data were not normally distributed. P values less than 0.05 are considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the initial series of subjects, the use of sampling intervals
of every 15 min and every 10 min resulted in a significant loss of
information regarding the number of pulses present in a given series
for both FAS and LH (Fig. 1
). There was
an overall decrease in the number of FAS pulses detected with
increasing sampling interval, as reflected by an increase in IPI
(53.8 ± 3.6, 69.2 ± 3.9, and 87.6 ± 7.3 min at
sampling intervals of 5, 10, and 15 min, respectively;
P < 0.0005). A significant effect was apparent
with each increment in sampling interval. Likewise, for LH, there was
an overall increase in IPI with increasing sampling interval (54.4
± 2.5, 70.4 ± 2.3, and 91.1 ± 4.4 min;
P < 0.0001), significant between each of the
different sampling intervals. When the 5-min sampling series was
truncated at 8 h, there was no difference in the calculated number
of pulses/24 h for FAS (26.0 ± 1.7 vs. 26.4
± 1.6 for 12- and 8-h series, respectively) or LH (25.0 ± 1.0
vs. 25.2 ± 1.1 for 12- and 8-h series,
respectively).
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In the second series of subjects studied, the difference in mean
age between the older and younger PMW was also reflected in the number
of years since menopause (Table 1). Two
of the younger PMW and three of the older PMW had had surgical
menopause, and there was no difference in E2,
E1, or BMI between the two groups. There was a
marked decrease in mean levels of all of the gonadotropins between the
45–55-yr-old and 70–80-yr-old PMW (Table 1). The decrease with aging
amounted to approximately 40% for LH, 37% for FSH, and 58% for
FAS.
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). The decreased frequency of pulsatile
FAS with aging is seen as an increase in IPI from 52.6 ± 3.1 min
(median, 49.4) in the younger PMW to 70.6 ± 5.9 min (median,
66.7) in the older PMW (Fig. 3;
P < 0.01) and as a significant shift in the
distribution of IPIs to longer intervals in the older subjects (Fig. 4). When the 5-min data from the two
series of studies were combined to provide a distribution across the
spectrum from 47–80 yr of age, there was a significant correlation of
IPI with age (r = 0.409; P < 0.02). For LH, the
difference in IPI between younger and older women was not statistically
significant [60.2 ± 8.9 min (median, 59.3) and 65.4 ± 5.6
min (median, 71.7), respectively; Fig. 3); there was more overlap in
the distribution of IPIs between the two groups, and the correlation of
age with IPI across the combined groups was not significant.
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] and LH [23.2 ± 3.1 IU/L
(median, 23.0) and 15.9 ± 2.1 IU/L (median, 13.6);
P = 0.09]. The decrease with age approximated 48% for
FAS and 30% for LH, suggesting a greater effect of aging on FAS than
on LH pulse amplitude. Interestingly, when pulse amplitude was
expressed as a percentage of pulse nadir, the effect of age on pulse
amplitude was no longer apparent for FAS (59% ± 8 and 54% ± 12),
whereas LH increased with age (31% ± 2 and 41% ± 4 for younger and
older PMW, respectively; P < 0.05). |
Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In the human, indirect methods must be used to assess hypothalamic GnRH secretion. Traditionally, measurement of LH pulse frequency has been used as a marker of antecedent GnRH stimulation to assess changes in GnRH pulse generator activity (25, 32, 33) based on its validation in a number of animal models in which peripheral LH secretion is closely correlated with central measurements of pulsatile GnRH (12, 13, 14, 15). Recently, FAS has also been used as a surrogate marker of pulsatile GnRH secretion in human studies (19, 25, 34). Direct validation in animal models has not yet been performed; however, there is increasing evidence that in euthyroid subjects the pulsatile component of FAS is controlled by GnRH, whereas TRH contributes to the more constitutive secretion of the hormone (18, 19). In PMW GnRH receptor blockade abolished pulses of FAS concomitantly with those of LH (22). These studies also showed that the degree of control of FAS by GnRH relative to TRH is greater in PMW than in normally cycling women. Taken together these observations indicate that FAS should reflect pulsatile GnRH secretion in PMW as it does in other subject populations. In GnRH-deficient men, we have now shown that FAS is not only a marker of antecedent GnRH stimulation, but is superior to LH at the fast frequencies of GnRH secretion that are encountered in PMW (23). These same studies provided evidence for desensitization of FAS secretion with fast frequency GnRH stimulation, as is widely known to occur for LH (35, 36). Thus, the ability of FAS to serve as a better marker of GnRH secretion is likely due to faster clearance of the subunit compared with that of intact gonadotropins (21, 22, 37). The differential clearance of FAS and LH becomes even more important in studies of aging in women because the half-life of plasma disappearance of LH is 2.5 times longer after menopause (22, 38), whereas that of FAS is unchanged (22). Consistent with this finding, individual studies in PMW shown here indicate that pulses of FAS are more clearly defined than are those of LH.
The current study reinforces the importance of sampling interval in assessment of episodic hormone secretion as the IPI for both LH and FAS was significantly shorter using a 5-min sampling interval when compared with both a 10- and 15-min series. Using FAS as a marker of GnRH secretion and a sampling interval of every 5 min, we have now demonstrated that pulses occur approximately every 50–55 min in younger PMW, similar to that which we have previously found in the late follicular phase and the midcycle surge in normally cycling women, also using FAS as a marker of GnRH secretion and a 5-min sampling interval (25). This estimate of GnRH pulse frequency is generally faster than the range of IPIs of 64–120 min reported in previous studies in menopausal women in which LH was used as the marker of GnRH secretion and blood was sampled at 10-min intervals (8, 10, 16, 39, 40). It is likely that the use of FAS and a 5-min sampling interval are the most important contributors to the higher postmenopausal pulse frequency found in the current study compared with previous studies. However, the use of only daytime sampling in the current series may also play a role because the frequency of pulsatile LH secretion has been found to be lower at night in menopausal women (16). Even in the younger PMW, GnRH pulse frequency is not as fast as has been described in 5-min sampling studies in agonadal men (41). In the current study, there were too few ovariectomized patients to determine whether the difference between PMW and castrate men is due to residual feedback from the postmenopausal ovary or to a primary difference in the maximum unrestrained frequency of GnRH pulse generator activity between men and women. However, because neither E2 nor E1 levels are altered by ovariectomy in PMW (5), there may well be an intrinsic difference in the unrestrained frequency of the GnRH pulse generator between men and women.
Menopause has historically been considered to be a primary ovarian event, with associated changes in pituitary gonadotropin secretion occurring secondary to the decline in ovarian sex steroids. However, the results of the current study add to a growing body of data that indicates that there are independent age-related changes in the hypothalamic-pituitary components of the human reproductive system. In this study, a 35% decline in the frequency of pulsatile FAS secretion between the 5th and the 8th decade in menopausal women provides evidence of a slowing of hypothalamic GnRH pulse generator activity. Whether this is accompanied by a decrease in the overall amount of GnRH secreted remains to be determined. The effect of age on GnRH pulse generator activity has been examined previously using LH as the marker of GnRH secretion, but with variable results. Alexander et al. (10) did not find an effect of age less than or greater than 50 yr on LH pulse frequency in ovariectomized women, although the numbers in each group were small and the sampling duration was only 5 h. Similarly, however, there was no difference in LH pulse frequency measured over 24 h in the studies of Santoro et al. (16), in which young women with premature ovarian failure were compared with women following normally timed menopause. In contrast, Rossmanith et al. (8) demonstrated a decline in LH pulse frequency with age comparing women aged 49–57 yr and 78–87 yr following natural menopause, although estimates of pulse frequency in both groups were considerably lower than in the current studies. Lambalk et al. (11) also demonstrated a decrease in LH pulse frequency with chronological age in menopausal women, although surprisingly mean gonadotropin levels were not inversely correlated with age in their series. We have assumed that the decline in GnRH pulse frequency is a direct effect of declining hypothalamic function and that it is not secondary to any changes in the low levels of circulating gonadal steroids. There was no effect of aging on E2 or E1 levels in the current study, and although androgen levels decrease with age following menopause (42), previous studies have failed to demonstrate an effect of androgen receptor blockade on LH pulse frequency or amplitude in PMW (43).
A decrease in LH pulse amplitude with aging in PMW has been described in one previous study (8), although not in others (10, 11, 16). In the current study, there is a decrease in amplitude of FAS and LH, although the change in LH amplitude reached significance only with one-sided testing (P < 0.03). There are two possible explanations for a decrease in pulse amplitude with aging—either a decrease in the amount of GnRH secreted with each secretory episode or a decrease in pituitary responsiveness to GnRH. When expressed as percent increase over baseline, there was no effect of age on FAS pulse amplitude, whereas that of LH increased with age. In previous studies, the LH response to exogenous GnRH has been used in an attempt to isolate the effect of age on pituitary responsiveness with conflicting results (8, 11). Interpretation of results of GnRH testing in the setting of endogenous pulsatile GnRH secretion may be compounded by the dependence of the pituitary response to GnRH on the preceding IPI (44). In the current setting, this would be particularly problematic due to the systematic difference in IPI between younger and older women. Thus, the question of whether the age-associated decrease in GnRH pulse frequency is accompanied by a decrease in pituitary responsiveness remains unresolved.
In conclusion, measurement of FAS as the primary marker of GnRH pulse generator activity and the use of a 5-min sampling interval indicate that GnRH pulse frequency is faster in younger PMW than previously appreciated, but is not increased over that seen in the late follicular phase and midcycle surge in normal cycling women. The decrease in FAS pulse frequency with age in PMW implies a decrease in GnRH pulse frequency and indicates that hypothalamic changes occur with aging that are independent of the changes in gonadal feedback that accompany the menopause. Whether this age-related change in GnRH pulse frequency is associated with a decrease in overall GnRH secretion and/or changes in pituitary responsiveness to GnRH remain to be determined.
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Acknowledgments |
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Footnotes |
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2 Present address: Procrea BioSciences Inc.,
Québec, H3P 3H5 Canada.
Received September 15, 1999.
Revised February 5, 2000.
Accepted February 10, 2000.
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References |
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-subunit secretion. J Clin Endocrinol Metab. 62:102–108.[Abstract]
-subunit secretion from the
gonadotrope by gonadotropin-releasing hormone (GnRH): evidence from the
use of two GnRH antagonists. J Clin Endocrinol Metab. 70:328–335.[Abstract]
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stimulation of the gonadotroph in the human: evidence from normal and
GnRH-deficient men. J Clin Endocrinol Metab. 70:1654–1661.[Abstract]
-subunit is superior to luteinizing hormone as a
marker of gonadotropin-releasing hormone despite desensitization at
fast pulse frequencies. J Clin Endocrinol Metab. 84:1028–1036. subunit of glycoprotein hormones
by assay with use of a monoclonal antibody. Clin Chem. 34:2022–2025.-subunit secretion in man. J Clin Endocrinol
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). Note the greater clarity of pulses detected with FAS
compared with LH.
