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From the Clinical Research Centers |
Reproductive Endocrine Unit (J.L.S., K.A.M., J.E.H.), and Oncology Division (J.G.S.), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Dr. Janet Hall, Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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-subunit (FAS), and the decline of
serum levels was monitored. The NAL-GLU GnRH antagonist ([Ac-D-2Nal1,D-4ClPhe2,D-3Pal3,Arg5,D-4-p-methoxybenzoyl-2-aminobutyric acid6,D-Ala10]-GnRH) was administered sc, at doses of 5, 15, 50, and 150 µg/kg, to 15 euthyroid PMW in 21 studies. Blood was sampled every 10 min, for 4 h before and 8 h after a single sc injection of the GnRH antagonist, followed by hourly samples, ending at 20 h after injection. Results of the maximally suppressive doses (50 and 150 µg/kg) were compared with those of 24 normal cycling women in the early follicular phase and late follicular phase or early luteal phase, and 8 women at the midcycle surge (MCS), who also received these doses of the GnRH antagonist. The best fit curve describing the decay of hormone serum levels after maximal GnRH receptor blockade was determined by nonlinear regression analysis.
The elimination of both LH and FAS, after GnRH receptor blockade, exhibited apparent first-order kinetics characterized by a single exponential phase. No differences were seen in percent suppression or half-lives (t1/2) of LH or FAS, between the 50- and 150-µg/kg antagonist doses, in any of the subject populations; and percent suppression of LH was similar across all groups. The t1/2 of LH was prolonged in PMW (139 ± 35 min, mean ± est. SD), in comparison with both the MCS (78 ± 20 min; P < 0.0005) and other cycle stages (57 ± 28 min; P < 0.0001). However, the disappearance of FAS was not different in PMW, compared with MCS or other cycle stages (t1/2 = 51 ± 26, 41 ± 12, and 41 ± 19 min, respectively).
Our conclusions were: 1) Disappearance of endogenous LH after GnRH receptor blockade is significantly prolonged in PMW, compared with the MCS or other cycle stages; 2) The disappearance of FAS is not altered in PMW, suggesting that differences in the disappearance of LH relate to LH microheterogeneity rather than systemic factors.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Considerably less is known about potential changes in the clearance of LH after the menopause. Studies in which LH clearance was assessed by a single bolus or constant infusion of 131I-labeled human LH indicate that clearance of exogenous hormone is not affected by menopausal status, but they do not address the question of whether there are changes in the clearance of endogenously secreted hormone after menopause (2, 4). It is known that multiple isoforms of LH, differing in their carbohydrate structure and charge, coexist in both pituitary and serum (5, 6). Further evidence suggests that biologic and immunologic activity, as well as hormone clearance, may vary in relation to changes in the carbohydrate structure of LH (7, 8), as has been demonstrated for FSH (9). For both LH and FSH, more basic isoforms are associated with shorter half-lives (t1/2). A greater preponderance of the less basic forms is seen in PMW, compared with normal cycling women (5), suggesting that the t1/2 of endogenous LH may be increased after menopause. This hypothesis is supported by studies showing that clearance of LH after hypophysectomy is prolonged in ovariectomized rats, compared with intact rats (10).
Although the t1/2 of endogenous LH has also been assessed in castrate women after hypophysectomy (2, 11), similar comparative data are not available in women with regular menstrual cycles. Modeling of LH clearance, using deconvolutional analysis of pulsatile data, suggests that the disappearance of endogenous LH is prolonged in PMW, compared with younger women (12). An alternative approach is to examine the disappearance of LH after GnRH receptor blockade, which inhibits endogenous LH secretion and permits a more direct assessment of hormone elimination.
Thus, to test the hypothesis that the plasma disappearance of
endogenous LH is decreased after menopause, GnRH receptor blockade was
instituted, using maximally suppressive doses of the
NAL-GLU GnRH antagonist
([Ac-D-2Nal1,D-4ClPhe2,D-3Pal3,Arg5,D-4-p-methoxybenzoyl-2-aminobutyric
acid6,D-Ala10]GnRH), and the decline of serum
LH was measured in PMW and normal cycling women. The decline in
glycoprotein free -subunit (FAS) was also assessed to investigate
possible age-related changes in clearance mechanisms.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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PMW. Twenty-one studies were performed in 15 healthy, euthyroid women, 49–68 yr old, all of whom were at least 2 yr post menopause. Four women had undergone surgical menopause. All subjects had been off any estrogen replacement for at least 6 months before the studies. The study was approved by the Subcommittee on Human Studies of the Massachusetts General Hospital, and all participants provided written informed consent.
Normal cycling women. Studies in PMW were compared with previously published results in 50 regularly cycling women, 18–40 yr old, who were studied in the early follicular phase (EFP), late follicular phase (LFP), and early luteal phases (ELP), (EFP+LFP+ELP combined as normally cycling women) and at the gonadotropin midcycle surge (MCS) (13). Women at the MCS were included, because their mean LH levels are comparable with those in PMW. All controls had normal TSH and PRL levels and had ovulated in the cycle before study, as evidenced by a midluteal-phase plasma progesterone level more than 6 ng/mL (>19 nmol/L) or a biphasic body temperature chart.
Experimental protocol
To determine the acute response to GnRH receptor blockade, the subjects were admitted to the General Clinical Research Center of the Massachusetts General Hospital. For each study, blood was sampled every 10 min, for 4 h before and 8 h after sc injection of 5, 15, 50, or 150 µg/kg of the NAL-GLU GnRH antagonist, followed by hourly samples, ending 20 h after the antagonist administration. Five to six studies were performed at each antagonist dose. For those women who participated in more than one study, studies were performed at least 30 days apart, to ensure recovery from any effect of the antagonist or blood drawing, and no subject was studied at the same dose on more than one occasion.
A total of 63 studies were performed in the control subjects in the EFP, LFP, and ELP; with 12, 23, 14, and 14 normal subjects studied at the 5-, 15-, 50-, and 150-µg/kg doses, respectively. Sixteen subjects who were studied at the MCS were compared separately.
Assays
Serum concentrations of LH, FSH, and FAS were measured by RIA, using a ß-directed LH polyclonal RIA, an intact-directed FSH polyclonal RIA, and a monoclonal RIA specific for FAS, as previously described (14, 15). All samples from an individual subject’s study were measured in duplicate in the same assay. The intraassay coefficients of variation for LH and FSH were between 4 and 7%; the interassay coefficients of variation for LH and FSH were between 3 and 6%. The LH and FSH assays had a sensitivity of 0.8 IU/L using the Second International Reference Preparation of human menopausal gonadotropin as the standard. For FAS, the intraassay coefficient of variation was 3–9%, and the interassay coefficient of variation was 4–12%. The sensitivity of the FAS assay was 30 ng/L. Estradiol (E2) was measured by RIA after extraction, as previously described (16). The sensitivity of the assay was 20 pg/mL.
Data analysis
To determine the extent of the LH, FAS, and FSH decrease after administration of the GnRH antagonist in PMW, the data for each patient were divided into a pretreatment 4-h baseline period and five 4-h periods after antagonist administration. Mean hormone levels from each time period were then compared, using ANOVA for repeated measures, followed by post hoc Newman-Keuls testing for individual differences.
The percent inhibition of each hormone was calculated for each dose, as previously described (13), by determining the nadir after antagonist administration, subtracting this from the mean baseline value, and expressing the difference as a percent of baseline. The nadir was determined for LH and FAS (using a 6-point moving average) and for FSH (using a 3-point moving average). There was no difference in the percent inhibition among the EFP, LFP, and ELP (13); therefore, the data from each dose during the different stages were combined and used for reference. The maximum percent inhibition was then compared among the three glycoprotein hormones and among PMW, the normal cycling women, and women at the MCS, using ANOVA.
Kinetic parameters describing the decrease of gonadotropin serum concentration after the administration of maximally inhibitory doses of the GnRH antagonist to normal cycling and PMW were determined by nonlinear least-squares regression of the raw data using the WinNonlin Version 1.1 software package (Scientific Consulting, Apex, NC). The empirical equation that best fit the observed time courses was established by visual inspection of the predicted profile, residual analysis, the sum of squared residuals, the degree of correlation between model parameters, and the magnitude of the coefficients of variation of the parameter estimates (17). Only subjects studied at doses of 50 or 150 µg/kg who demonstrated full GnRH receptor blockade (defined by the absence of pulsatile secretion, as assessed by CLUSTER 2x2 analysis) were included in the final analysis. There was no difference in t1/2 of LH or FAS among normal cycling women in the EFP, LFP, and ELP; and these cycle stages were combined. Thus, the characteristics of LH disappearance were analyzed in 10 PMW, 24 normal cycling women, and 8 MCS studies. FAS disappearance rates were analyzed in 9 PMW, 10 normal cycling women, and 6 MCS subjects; and the results were compared with those of LH, using unpaired t tests. Because FAS results were available in fewer subjects than LH, a matched comparison was also performed using only subjects in whom both were available.
Hormone levels and percent inhibition are expressed as the mean ± SEM unless otherwise specified. Mean values of the apparent gonadotropin t1/2 for each group of subjects were calculated as harmonic means and are reported together with the jackknife estimate of the standard deviation (18). A P value < 0.05 was considered to be significantly different.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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At baseline, the 15 PMW were an average of 12.3 (range, 2–22) yr from menopause, with an LH of 66.1 ± 4.3 IU/L (mean ± SEM); FSH, 127.4 ± 10.7 IU/L; and FAS, 874.3 ± 86.1 ng/L. E2 was at or below the limit of detection (20 pg/mL) in all subjects, with the exception of 1 woman studied 7 yr after her last episode of menses, whose E2 level was 33 pg/mL. At baseline, LH, FSH, FAS, or E2 did not differ among dose groups.
Inhibition of LH, FSH, and FAS by GnRH receptor blockade in PMW
GnRH receptor blockade in PMW resulted in a decrease in LH in
response to all doses of the NAL-GLU GnRH antagonist (P
< 0.0001; Fig. 1
). At each dose, LH
levels remained significantly lower than baseline, for up to 20 h
post antagonist (P < 0.0002). However, at the two
lower doses, some recovery occurred within the 20-h sampling window.
Pulsatile secretion of LH was abolished in all subjects at the 50- and
150-µg/kg antagonist doses.
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), without evidence of significant
recovery during the 20 h of observation after antagonist
administration at any dose.
FAS was suppressed at all doses of the antagonist (P <
0.03 for doses of 5 and 15 µg/kg; P < 0.005 for 50
and 150 µg/kg; Fig. 1). At the highest two doses, FAS remained fully
suppressed for the duration of the study. Only one postmenopausal
subject demonstrated continued pulsatile secretion of FAS after the two
highest doses of the NAL-GLU antagonist (and was therefore excluded
from analysis of hormone disappearance).
Maximum percent inhibition
The maximum percent inhibition of LH after GnRH antagonist
administration in the PMW (Fig. 2) was
similar between doses of 5 and 15 µg/kg (58.9 ± 2.7 and
59.5 ± 3.5%, respectively) and significantly less than that seen
with a dose of 50 µg/kg (75.2 ± 3.4%; P <
0.01). There was no further suppression at the 150-µg/kg dose
(78.6 ± 1.5%). The maximum percent inhibition of LH at the
150-µg/kg dose was not different between PMW and normal cycling women
(80.7 ± 1.7%) but was somewhat greater at the MCS (84.3 ±
1.3; P < 0.05 vs. PMW). The maximum percent
inhibition of FAS was similar between doses of 50 and 150 µg/kg. The
maximum inhibition at the highest antagonist dose was significantly
greater in PMW than in normal cycling women (49.2 ± 2.4
vs. 29.3 ± 2.7%; P < 0.001) but not
different from the MCS (51.5 ± 4.1%). The maximum percent
inhibition of FSH occurred at an antagonist dose of 50 µg/kg, with no
further suppression at the 150-µg/kg dose in PMW. There was no
difference in maximum percent inhibition of FSH between PMW and normal
cycling women (40.6 ± 1.6 and 43.6 ± 2.8%), whereas
percent inhibition was greater at the MCS (53.4 ± 4.8%;
P < 0.05), as previously described (13).
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Expression of the data as percent of baseline revealed the
existence of a marked difference in the pattern of hormone
disappearance after GnRH receptor blockade, between PMW and normal
cycling women, for LH (Fig. 3) but not
for FAS. Serum concentration-time courses of LH and FAS, in subjects
who received 50 and 150 µg/kg of the NAL-GLU GnRH antagonist, were
analyzed to characterize their elimination kinetics. After antagonist
administration, the rapid decline of serum LH and FAS concentrations
(C) to a constant nadir level (Cmin)
was best described in all subjects by an equation with a single
exponential term:
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. Development of a more highly
descriptive pharmacodynamic model was precluded because sampling was
discontinued at 20 h after dosing, before serum LH and FAS
concentrations began to recover, and the drug concentration was not
measured. Because FSH continued to decline and did not approach a nadir
during the course of this study, a t1/2 was not
modeled.
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. In PMW, the t1/2 of
LH was 139.1 ± 35.4 min and was significantly prolonged, in
comparison with both the normal cycle (56.9 ± 28.4 min;
P < 0.0001) and the MCS (77.5 ± 20.1 min;
P < 0.0005). The LH t1/2 at the MCS
was also significantly longer than at the other cycle stages
(P < 0.01).
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). In contrast to LH,
there was no difference in the t1/2 of FAS among
PMW, normal women, and women at the MCS (50.5 ± 25.8, 41.2
± 12.0, and 40.7 ± 19.1 min, respectively). All statistical
differences remained significant in the matched comparison using only
subjects with both LH and FAS data. |
Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The prolonged disappearance of LH in PMW is most likely caused by differences in the isoform composition of secreted LH. Exogenous injection of different LH isoforms in animal studies has shown that the metabolic clearance rate varies with isoform (19). In general, animal studies have shown that more basic forms of both LH and FSH yield a greater in vitro potency, but shorter t1/2 in circulation, whereas more acidic isoforms have a longer circulatory time and are more active in in vivo estimations (7, 20). Changes in isoform composition, to more acidic forms, may be caused by decreased activity of the GalNAc-transferase, with subsequent increases in LH sialic acid content (21). The longer t1/2 of LH in PMW in the current studies is consistent with the presence of a preponderance of the more acidic forms of LH, which have been described in PMW (5, 22).
In the current studies, we have defined the dose-response relationship for GnRH receptor blockade, using the NAL-GLU GnRH antagonist in PMW, and we demonstrated that a dose of 50 µg/kg causes maximum suppression, with no further change at 150 µg/kg. At these doses, pulsatile secretion of LH was abolished for up to 20 h; and serum LH values declined, to a constant nadir, permitting evaluation of the elimination rate constant. The maximum degree of LH suppression in these studies is similar to that reported previously for both immunoactive (23, 24, 25) and bioactive (26) LH in PMW and normal cycling women (13, 27) using a variety of potent GnRH antagonists. Although it is known that secretion of FAS is under the dual control of GnRH and TRH, the current studies, in which FAS pulses were abolished by the highest doses of the GnRH antagonist, provide additional support for the hypothesis that the pulsatile component of FAS secretion is predominantly controlled by GnRH (28, 29). Maximum inhibition of FAS was greater in both PMW and at the MCS, in comparison with normal cycling women. These results suggest that, in these situations, in which the pituitary response of LH to GnRH is enhanced (3, 30), GnRH also contributes a greater proportion to overall FAS secretion, whereas the thyrotrope contribution of FAS remains fixed.
The use of GnRH receptor blockade is analogous to the limited number of studies in which the disappearance of endogenous LH was calculated after hypophysectomy (11), but it has the advantage of permitting comparison with normal women. Previous studies, which have used deconvolution techniques on individual pulses, have estimated the LH t1/2 as 150–171 min in PMW (slightly longer, but generally consistent with the current studies) (12, 31). Estimation of t1/2, using blockade of LH secretion, offers the advantage (over deconvolution techniques) of more direct measurement and increased accuracy, because of an increased number of samples in the decline and the ability to follow the decline over several half-lives.
At the maximally inhibitory doses of the NAL-GLU antagonist, a small amount of residual LH persists. Residual LH may result from non-GnRH-dependent secretion, forms of LH with an extremely long clearance, or lack of complete blockade of the GnRH receptor by this antagonist. If the GnRH receptor is not completely blocked by the GnRH antagonist, ongoing secretion could potentially influence the calculated t1/2 of LH. However, because the rate of decline of LH is so rapid after GnRH antagonist administration, the rate constant of formation would be insignificant, relative to that of elimination. In addition, both the maximum percent inhibition and the absolute residual LH concentration were similar in the postmenopausal and MCS subjects; and thus, this mechanism could not account for the prolonged t1/2 of LH in PMW, compared with the MCS.
In the current studies, the disappearance of LH after GnRH receptor blockade was markedly prolonged in PMW, compared both with normal cycling women and with women at the MCS. Previous studies have suggested that clearance mechanisms are saturable at high plasma hormone concentrations (32). Thus, women studied at the MCS served as an important control group, because mean LH was similar to that in PMW, suggesting that the observed decrease in clearance in PMW does not result from saturation of clearance mechanisms.
The t1/2 of FAS is significantly shorter than that
of LH in both PMW and normally cycling women, consistent with studies
in which clearance of LH and FAS was estimated from endogenous
pulsatile secretion in GnRH-deficient men receiving exogenous GnRH
(33). We have only assessed that portion of FAS that is presumed to be
derived from the gonadotrope in these studies. Importantly, the
estimated t1/2 of FAS was similar between studies in
which TSH- or LH- were infused into normal subjects (4, 34),
suggesting that the cellular source of FAS may not influence its
clearance characteristics. Mean FAS is elevated both in PMW and in
women studied at the MCS; and thus, the disappearance of FAS, as for
LH, is not influenced by mean level.
Previous studies, assessing gonadotropin t1/2, have
variously reported one and two components of clearance. Where reported,
the first component t1/2 ranges from 10–60 min (2, 11, 20, 35) and is attributed to either serum distribution or hepatic
clearance. Use of a receptor blockade model and an endogenously
pulsatile environment may have masked this rapid component in the
current studies. Pituitary glycoprotein hormones are cleared by both
renal (36, 37) and hepatic (38, 39) mechanisms. Previous studies failed
to demonstrate an effect of menopause on clearance of exogenous TSH-
(34) or an effect of gender on clearance of exogenous hCG- (40). In
men, age did not affect clearance of endogenous FAS, assessed by
deconvolution (41). These results are consistent with the lack of
effect of physiologic state on the disappearance of endogenous FAS in
the current studies, and they imply that renal and/or hepatic handling
of glycoprotein hormones is not generally impaired secondary to age or
gonadal hormone status in PMW. Metabolic clearance of exogenous LH is
not different in PMW (2, 4) or ovariectomized animals (10), in
comparison with the gonadally intact state, supporting this conclusion
and suggesting that the prolonged disappearance of endogenous LH in the
current studies must be caused by changes in the isoform composition of
LH secreted in PMW.
In summary, the GnRH antagonist provides a unique physiologic probe that permits inferences to be made about the disappearance of the secretory products of the gonadotrope. The t1/2 of endogenous LH, after GnRH receptor blockade, is significantly prolonged in PMW, compared with the MCS or other cycle stages, whereas the disappearance of FAS does not change. These data suggest that differences in the disappearance of LH in PMW relate to changes in LH microheterogeneity, rather than systemic factors. Further studies will be required to determine whether changes in LH disappearance in PMW are related to effects of aging or loss of gonadal feedback.
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Acknowledgments |
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Footnotes |
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Received July 15, 1998.
Revised September 15, 1998.
Revised October 16, 1998.
Accepted October 16, 1998.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-subunit. Glycobiology. 5:3–10.-subunit in postmenopausal
women. Clin Endocrinol (Oxf). 34:477–483.[Medline]
-subunit as an
alternative neuroendocrine marker of gonadotropin-releasing hormone
(GnRH) stimulation of the gonadotroph in the human: evidence from
normal and GnRH-deficient men. J Clin Endocrinol Metab. 70:1654–1661.[Abstract]
that mediates rapid
clearance of lutropin. Cell. 67:1103–1110.[CrossRef][Medline]
-subunit release in young vs. older men: appraisal with
high-specificity immunoradiometric assay and deconvolution analysis. Eur J Endocrinol. 135:399–406.[Abstract]
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), and women at the MCS (
) (mean ±
SEM). Maximum percent inhibition of LH was not different
between groups. In PMW, percent inhibition of FAS at the highest
antagonist dose was greater than in normal cycling women but not
different from women at the MCS.
