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From the Clinical Research Centers |
-Subunit Is Superior to Luteinizing Hormone as a Marker of Gonadotropin-Releasing Hormone Despite Desensitization at Fast Pulse Frequencies1
Reproductive Endocrine Unit and National Center for Infertility Research, and Department of Biostatistics, General Clinical Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114
Address correspondence and requests for reprints to: Frances J Hayes, MB, MRCPI, Reproductive Endocrine Unit and the National Center for Infertility Research, Massachusetts General Hospital, BHX 5, 55 Fruit St., Boston, Massachusetts 02114.
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Abstract |
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-subunit (FAS).
The aims of this study were to determine whether the FAS response to
GnRH is also decreased at fast frequencies of GnRH stimulation and
whether FAS is superior to LH as a marker of GnRH secretory activity at
fast-pulse frequencies. The model of GnRH-deficient men was chosen to
permit precise control of the dose and frequency of GnRH stimulation of
the gonadotrope. The frequency of iv administration of GnRH to 5
GnRH-deficient men was progressively increased from every 120 to every
60 min, from 60 to 30 min, and from 30 to 15 min during three 12-h
admissions, 1 week apart. The bolus dose of GnRH remained constant and
was set at that dose previously shown to produce physiological
concentrations and amplitudes of LH secretion and normal testosterone
levels. As the frequency of GnRH stimulation was increased, a progressive rise in mean FAS levels was noted (353 ± 13, 448 ± 42, 466 ± 50, and 698 ± 85 ng/L [mean ± SEM] for 120, 60, 30, and 15 min intervals; P < 0.005). However, normalization of mean FAS levels to account for the increase in total GnRH delivered with increasing frequencies revealed a progressive decrease in pituitary responsiveness to each GnRH bolus with increasing frequency of stimulation (353 ± 13, 224 ± 21, 117 ± 13, 87 ± 11 ng/L; P < 0.001). The decrease in normalized mean levels was supported by a decrease in the FAS pulse amplitude with increasing frequency (517 ± 53, 365 ± 50, 176 ± 29 ng/L for 120, 60, and 30 min intervals, respectively; P < 0.005).
At interpulse intervals of 120 and 60 min, there was complete concordance of LH and FAS pulses in response to GnRH. However, at the 30-min frequency FAS proved to be a better marker of GnRH with a higher true positive rate and lower number of false positives than LH (P < 0.05). At all frequencies, the number of false positive pulses detected tended to be lower for FAS than for LH (P = 0.06).
From these data we conclude that FAS is subject to desensitization in response to increasing frequencies of GnRH administration in GnRH-deficient men, but is superior to LH as a surrogate marker of GnRH pulse generator activity at fast pulse frequencies.
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Introduction |
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While there is concordance between secretion of LH and the glycoprotein
free -subunit (FAS) under physiological conditions (18, 19, 20, 21), these
two hormones appear to be differentially sensitive to desensitization.
Unlike LH, most studies using chronic GnRH agonist administration have
concluded that FAS escapes GnRH-induced desensitization. Human studies
using GnRH agonists in menopause (22, 23), and in patients with
endometriosis (24) and precocious puberty (25, 26) have reported
persistent elevation of FAS despite suppression of LH levels. These
human studies stand in contrast to pituitary perifusion studies in the
rat, which demonstrated parallel desensitization of the FAS and LH
responses to continuous GnRH administration (27). Importantly, the
human studies were all long-term in nature (weeks to months), whereas
the in vitro rat studies occurred over hours to days.
LH has traditionally been used as a surrogate marker of GnRH pulse generator activity (28, 29, 30, 31, 32, 33, 34), based on its validation in several animal models to faithfully mirror GnRH secretion (35, 36, 37). Recent studies have shown that FAS pulses are tightly correlated with those of LH (18, 19, 20, 21). Unlike LH, FAS secretion is under the dual control of GnRH and TRH (38, 39, 40, 41). However, GnRH appears to be the primary regulator of the pulsatile component of FAS secretion, as evidenced by the absence of FAS pulses in GnRH-deficient men and their restoration with GnRH administration (42, 43), as well as the eradication of pulsatile FAS activity in normal subjects by GnRH receptor blockade (44). We have previously hypothesized that FAS may be a better marker of the GnRH pulse generator in situations where GnRH secretion is rapid (45). This hypothesis predicts that measurement of FAS will prove a more accurate marker of GnRH secretion in postmenopausal women (15, 46), agonadal men (16), and in polycystic ovary syndrome (17, 47). FAS could potentially be a better marker of GnRH at fast frequencies by virtue of its shorter half-life (19, 48, 49, 50) or because of a failure to desensitize.
The aim of the present study was to reconcile the conflicting in vivo and in vitro data on FAS desensitization using the human model of GnRH-deficient men, which permits precise control of both the dose and frequency of acute and chronic GnRH stimulation of the pituitary. These studies also allowed us to address the issue of whether FAS is superior to LH as a marker of GnRH secretory activity at fast-pulse frequencies.
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Materials and Methods |
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Five men ages 25–30 yr with isolated GnRH deficiency as previously described were studied (14). All had absent endogenous gonadotropin pulsations on frequent blood sampling for 16–24 h at the time of diagnosis. At the time of participation in the study all subjects had normal gonadotropin and sex steroid concentrations for at least 3 months while receiving long-term sc pulsatile GnRH at 120-min intervals. The protocol was approved by the Subcommittee on Human Studies of the Massachusetts General Hospital, and all subjects provided written informed consent.
Protocol
Each subject was studied during three 12-h admissions, one week apart as previously described (14). Three days before the first admission, an indwelling catheter was inserted into a forearm vein to convert subjects from long-term sc to iv GnRH. GnRH was administered at 120-min intervals by a portable infusion pump (Ferring Laboratories, Inc., NJ). The iv route of administration was chosen as it eliminates pharmacokinetic considerations that im or sc routes raise. In addition, iv administration of GnRH produces gonadotropin responses that more closely mimic the spontaneous LH pulses of normal men than do sc injections (51). For each subject, the GnRH dose used was that previously shown to produce LH pulse amplitudes within the midrange of normal men (52) and ranged from 17–22 ng/kg/bolus. This bolus dose of GnRH was kept constant throughout the study.
On day 1 of the study, subjects were admitted to the General Clinical Research Center of the Massachusetts General Hospital. GnRH was injected manually at 120-min intervals for the first 6 h, then every 60 min for the subsequent 6 h. The initial dose interval of 120 min was chosen as it is the mean LH interpulse interval in normal men (33, 53). Subjects were then discharged on iv pulsatile GnRH at 60-min intervals for the next 7 days. During the second 12-h admission (day 8), GnRH was injected every 60 min for the first 6 h and every 30 min for the subsequent 6 h. The subjects then received iv GnRH at 30-min intervals as outpatients for the following 7 days. During the final admission (day 15), GnRH was injected every 30 min for the first 6 h, increasing to every 15 min for the last 6 h. One subject was not studied during the 15-min dosing interval due to blood volume considerations.
Serum gonadotropin concentrations were determined every 10 min when GnRH was administered at 120- and 60-min intervals, and every 5 min at frequencies of 30 and 15 min. Serum testosterone (T) concentrations were determined on serum pools comprising equal aliquots of each sample obtained during each 6-h sampling period.
Assays
All samples from each individual were analyzed in duplicate in a
single assay. Serum LH was determined using a highly specific RIA with
the Second International Reference Preparation as the reference
standard, as previously described (31). The assay sensitivity for LH
was 0.8 mIU/mL, and both inter- and intraassay coefficients of
variation (CV) were less than 6%. Serum FAS concentrations were
determined by a monoclonal antibody RIA using highly purified
-subunit of hCG as the assay calibrator as previously described (54, 55). The assay sensitivity for FAS was 30 ng/L. Intra- and interassay
variance were determined using aliquots of 3 pools of human serum
containing 234 (
80% B/B0), 444 (50%
B/B0), and 851 (20% B/B0) ng/L. The
intraassay CV was 7–8%, and the interassay CV was less than 15% for
all 3 levels of quality control sera. The FAS assay was highly specific
with cross-reactivities of 0.67% for human LH (hLH), 2.32% for hFSH,
and 0.36% for hTSH. The cross-reactivity of LH in the FAS assay was
caused entirely by the known FAS contamination of the LH preparation
and label as previously described (54). Serum T concentrations were
measured by a previously described RIA with an assay sensitivity of 10
ng/dL and an intra- and interassay CV of less than 15% (56).
Data analysis
Each 12-h sampling period was divided into 2 phases of equal duration corresponding to the specific GnRH dosing intervals. The 60-min and 30-min dosing intervals were further characterized into acute and chronic phases. The acute phase reflected the hormone concentrations during the first 6 h after an increase in GnRH pulse frequency, while the chronic phase reflected the hormone levels pertaining after 7 days of GnRH administration at that frequency.
The arithmetic means of serum LH and FAS concentrations were calculated for all dosing intervals. After each acute change in GnRH frequency, only the last 4 h of the 6-h sampling period were used for these calculations to allow gonadotropin levels to reach a new steady state. Serum sex steroid concentrations were also compared during successive 6-h sampling periods.
Throughout this study the bolus dose of GnRH was kept constant. However, when the frequency of exogenous GnRH administration is increased, the total amount of GnRH administered over any given time period also increases even though the individual bolus dose remains constant. To take this into account, a frequency-normalized mean was derived as previously described (14). Assuming that gonadotropin clearance remains constant throughout the study, the mean LH and FAS concentration (C) is proportional to the frequency (f) of GnRH administration and the amount (a) of hormone secreted during each pulse (C = f x a). Therefore, to normalize mean LH and FAS concentrations for different frequencies of GnRH administration, we divided the concentration by 2 every time the frequency was doubled. According to this concept, if pituitary responsiveness remains constant as GnRH pulse frequency is doubled, frequency-normalized means should not change while mean levels would be expected to double.
Pulsatile hormone secretion was analyzed at the 120-, 60-, and 30-min dosing intervals using three pulse detection algorithms, Cluster (57), Ultra (58), and the modification of the Santen & Bardin method (53) used in our previous studies (20, 21). To minimize the number of false positive pulses, this modification requires each peak to contain 2 points as previously described (21). The first point has to be at least 3 times the intraassay CV above the preceding nadir and must exceed it by at least 1 IU/L for LH and at least 30 ng/L for FAS; the second point may fulfill either one of these criteria. In the Cluster program, cluster sizes of 2 x 2 and 2 x 1 were used with a t-statistic of 2 for the upstroke and downstroke (57). For the Ultra program, the data were analyzed using both a 2-CV and 3-CV threshold (58). For all pulse detection programs, a true positive pulse was defined as the first gonadotropin pulse detected within 30 min of administration of a GnRH dose; all other pulses were considered to be false positives. The mean amplitude of LH and FAS pulses was also analyzed to assess pituitary responsiveness to each bolus dose of GnRH. In analyzing changes in pulse amplitude (defined as the difference between the peak and the preceding nadir) across frequencies, only true pulses detected by the Cluster (2 x 2) program were used.
Statistical analysis
Arithmetic means, normalized means, and mean pulse amplitudes were evaluated at each frequency of GnRH administration using analysis of variance for repeated measures followed by post-hoc Newman-Keuls testing for individual differences. A paired two-tailed t test was used to compare these 3 parameters during acute and chronic GnRH administration at the 60- and 30-min pulse frequencies.
The true positive rate and number of false positive pulses obtained with each pulse program were analyzed using repeated measures analysis of variance. At each dosing interval, true positive rates were derived from the number of true positive pulses detected, as a percentage of the number of GnRH doses administered at that frequency. False positive pulses were expressed as an absolute number at each frequency rather than as a rate. Given that the false positive rate is a function of the number of pulses present in a given series and that only 3 and 6 pulses, respectively, would be expected to occur during the 120- and 60-min dosing intervals, we felt that use of a false positive rate would be misleading. For statistical analysis, true positive rates were transformed using the arcsine square root transformation, and false positives were transformed using the square root transformation to stabilize the variance.
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Results |
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Arithmetic and normalized means. A progressive rise in mean
FAS levels was seen with increasing GnRH pulse frequency (355 ±
13, 448 ± 42, 466 ± 50, and 698 ± 85 ng/L [mean
± SEM] at 120-, 60-, 30-, and 15-min intervals,
P < 0.005; Figs. 1
and 2). A similar pattern was previously reported for LH
(11.7 ± 1.2, 17.5 ± 1.8, 31.5 ± 3.4, and 46.8 ±
10.2 IU/L; P < 0.005) (14). When mean levels were
normalized for the increase in total GnRH delivered at faster
frequencies, a progressive decline in pituitary responsiveness with
increasing frequency was noted for both FAS (355 ± 13, 224
± 21, 117 ± 13, and 87 ± 11 ng/L; P <
0.0001) and LH (11.7 ± 1.2, 8.8 ± 0.9, 7.9 ± 0.8,
5.8 ± 1.3 IU/L; P < 0.008 at 120-, 60-, 30-,and
15 min intervals, respectively), (Fig. 2).
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). A
corresponding decrease was observed in LH pulse amplitude (15.5 ±
2.0, 11.4 ± 1.2, and 10.1 ± 0.8 IU/L) as previously
described (14). Sex steroids. Testosterone levels were 653 ± 90, 650 ± 115, 964 ± 185, and 1207 ± 238 ng/dL, at 120-, 60-, 30-, and 15-min intervals, respectively (P < 0.05). T levels at the 15-min interval of GnRH administration were significantly higher than those seen at either the 120- or 60-min pulse intervals (P < 0.05); no other differences were observed.
Pulse analysis. At intervals of 120 and 60 min, each bolus of
GnRH was associated with clear discrete pulses of both FAS and LH (Fig. 1). However, as the frequency of GnRH administration was increased to
30 min, this 1:1 relationship was lost, with each dose of GnRH no
longer being predictably followed by a detectable pulse. Pulsatile
secretion of FAS was better preserved than that of LH at the 30-min
frequency (Fig. 3). Secretion of both LH and FAS
became very erratic when GnRH was administered every 15 min. Although
pulses were rarely evident at this frequency, a shorter sampling
interval would have been required for optimal pulse detection at such a
rapid frequency, and therefore the data from the 15-min study were
excluded from pulse analysis calculations.
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).
At the 30-min frequency, however, the true positive rate was higher for
FAS than for LH with all programs (P < 0.05). For FAS,
the true positive rate was independent of the algorithm used (range
92–97%), while for LH, the true positive rate varied with the pulse
detection program with a range of 70–89% (P < 0.02),
(Fig. 4).
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). There was a trend for the
number of false positives to be lower for FAS than LH
(P = 0.06), (Fig. 4). There was a difference in the
number of false positive pulses detected by the different programs for
both FAS (P < 0.05) and LH (P <
0.005), with the highest number obtained with the Ultra program (Fig. 4). II. Effect of acute vs. chronic GnRH administration
Mean LH levels did not differ between acute and chronic dosing (17.4 ± 1.8 vs. 20.3 ± 0.6 and 31.4 ± 3.4 vs. 35.9 ± 5.7 IU/L, acute vs. chronic studies at the 60- and 30-min pulse intervals, respectively), although there was a decrease in the true positive rate with chronic administration (P < 0.05). There was no difference in normalized means or LH pulse amplitudes between acute and chronic GnRH administration at either dosing interval (14). For FAS, there was a decrease in mean levels between acute and chronic studies at the 60-min frequency only (448 ± 42 vs. 362 ± 17 ng/L; P < 0.05). In keeping with the reduction in mean levels, a decrease was observed in normalized FAS mean levels (224 ± 21 vs. 181 ± 9 ng/L; P < 0.05) and FAS pulse amplitude (365 ± 50 vs. 236 ± 23 ng/L; P < 0.05), although there was no decrease in true positive pulse detection.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The demonstration that FAS is subject to desensitization when GnRH is administered at fast frequencies to GnRH-deficient men is consistent with the in vitro demonstration that FAS and LH show a similar degree of desensitization in response to continuous infusions of GnRH in perifused rat pituitary cells (27). In the perifusion studies, both the concentration-response and the time-course characteristics of desensitization were indistinguishable for LH and FAS (27). However, these data indicating desensitization of both LH and FAS in GnRH-deficient men are in conflict with previous human studies using long-acting GnRH agonists in a variety of physiological and pathological conditions (22, 23, 24, 25, 26). After a transient stimulatory effect, GnRH agonist administration resulted in a decrease in mean LH levels, which became refractory to exogenous GnRH, while FAS levels remained elevated and retained responsiveness to GnRH administration (25, 26). However, reexamination of the data reveals that in the few instances in which pulsatile glycoprotein hormone secretion was examined after GnRH agonist administration, endogenous pulsatile secretion of FAS was abolished (22, 25), and the amplitude of the FAS response to exogenous GnRH was decreased (25, 26). Applying the definition of desensitization as a decrease in gonadotrope responsiveness to a given bolus of GnRH, the abolition of pulsatile FAS activity and decreased response to a pharmacological dose of GnRH provided evidence for partial desensitization of FAS even in the setting of chronic agonist therapy. However, the fact that mean FAS levels remained elevated while LH levels decreased on chronic GnRH agonist therapy suggests that the degree of desensitization of FAS secretion was substantially less than that of LH.
A difference in the time course of desensitization of LH and FAS may explain the parallel increase in mean levels and the decrease in amplitude for LH and FAS in this and the perifusion studies, in contrast to the decrease in mean LH and increase in mean FAS seen with more chronic exposure to GnRH. In support of this hypothesis, experiments using plated cell culture have shown that differential secretion of LH and FAS in that model occurred only after 36–48 h of constant GnRH stimulation, at which point FAS levels continued to rise in response to GnRH, while LH did not (60). Therefore, it is possible that a decrease in mean LH without a decrease in FAS would have occurred if fast-frequency stimulation had been continued for a longer duration. Indeed, in 2 of the 5 subjects mean LH levels had already begun to decrease between the acute and chronic phases of GnRH stimulation at the 30-min pulse frequency, while mean FAS levels remained stable. In addition, LH was a poorer marker of antecedent GnRH stimulation than FAS in the chronic as compared to acute studies.
Although a valuable human model, there are limitations inherent in using GnRH deficient men to examine desensitization, notably the potential confounding variable of a changing sex steroid milieu as well as the exaggerated FAS response to GnRH reported in GnRH deficient men (20, 61). In the present study, testosterone levels rose when the frequency of GnRH stimulation was increased to 30 min. Previous studies of GnRH deficient men have shown that mean LH pulse amplitudes decreased by approximately 30% when testosterone levels were increased to approximately 1500 ng/dL using a continuous testosterone infusion (62). Therefore, one possible interpretation of our data is that the decrease in the amplitude of the LH response may be explained by a decrease in pituitary sensitivity as a result of sex steroid-mediated negative feedback. However, several factors argue against this interpretation. First, during the 60-min dosing interval, a period in which mean T levels were unchanged from the 120-min dosing interval, mean pulse amplitudes had already decreased by approximately 25% for LH and 30% for FAS. Second, mean LH and FAS amplitudes at the 30-min interval were 40 and 60% lower than baseline. This degree of gonadotropin suppression was significantly greater than that seen in the testosterone infusion study, where similar T levels were achieved but the frequency of GnRH administration was maintained at 120 min (62). In addition, while the testosterone infusion study revealed that each GnRH dose was consistently followed by an LH pulse albeit of decreased amplitude, this was not the case in the present study where up to 30% of LH pulses were not even detected. Finally, studies conducted in a perifusion system, which permits glycoprotein hormone secretion to be examined in an environment isolated from the effects of gonadal steroids and metabolic clearance considerations, have demonstrated similar desensitization of LH and FAS (27). While GnRH-deficient men have an exaggerated FAS response to exogenous GnRH, the mechanism for this FAS hypersecretion does not appear to be desensitization, as FAS maintains its pulsatile response to GnRH and the increase in FAS secretion is observed in GnRH-deficient subjects even at GnRH doses that result in a subnormal LH response (61, 63).
The demonstration that pulsatile secretion of FAS is tightly correlated with that of LH (18, 19, 20, 21) and is driven by GnRH (41, 42, 43, 44, 45) provides us with a second surrogate maker of GnRH pulse generator activity. We have previously shown that more FAS than LH pulses are detected in women during the midcycle surge (21), suggesting that FAS may be a better marker of GnRH when GnRH secretion is rapid. In the present study, we have shown that at frequencies of 120 and 60 min, the physiological range of frequencies observed in men (33, 53, 64, 65, 66) and in much of the menstrual cycle (30, 31, 32, 67, 68), LH and FAS are equally good markers of GnRH. However, at faster GnRH pulse frequencies, FAS is superior to LH as a marker of antecedent GnRH secretion regardless of the pulse detection program used. The superiority of FAS as a peripheral readout of hypothalamic GnRH secretion even in the face of some degree of desensitization likely reflects its shorter half-life. In studies using a variety of techniques including single injection or constant infusion of labeled hormone (48, 49), deconvolution analysis (19), or decay following GnRH receptor blockade (50), the half-life of FAS in normal men and women has been estimated to be 2- to 4-fold shorter than that of LH. This more rapid decay of FAS thus enables sharper resolution of secretory pulses that may be obscured for LH. Thus, FAS represents an ideal marker of GnRH secretion in both physiological and pathophysiological states of rapid GnRH secretion.
Over the years a number of algorithms have been developed for analysis of pulsatile hormone secretion (53, 57, 58, 69). As with all statistical methods, these algorithms are susceptible to false positive errors (i.e. detecting a pulse where there is none) and false negative errors (i.e. failing to detect existing pulses). One of the major limitations of pulse identification to date has been the difficulty in independently verifying true spontaneous hormone signals. Therefore, attempts to compare the performance characteristics of pulse analysis programs have largely relied on the use of simulated data comprising signal-free, randomly varying noise and/or physiological data where the precise pattern of endogenous GnRH pulse frequencies is not known (70). The underlying assumption of these validations is that the number of false positive pulses detected in these simulated data series provides a valid estimation of the false positive error when analyzing real series of hormonal data. However, with the demonstration that the false positive rate is a function of both the number and amplitude of the pulses present (58, 71), it is now known that this assumption is not valid and that the false positive error in noise series, in fact, greatly overestimates that in series with true pulses. The practical implication of these findings is that use of detection thresholds designed to curtail the false positive rate in noise series to approximately 1% is likely to underestimate the true pulse frequency in real data series (58).
The human model of GnRH-deficient men used in this study provides the unique opportunity to calculate both true and false positive pulses using a physiological, as opposed to signal-free, data set as has previously been done to validate deconvolution analysis of LH secretion and half-life (72, 73). The present study afforded us the opportunity to evaluate the performance of the modification of the Santen & Bardin method used in many of our previous studies (17, 20, 21, 31, 33) across a wide range of GnRH pulse frequencies and to compare it to other programs previously evaluated using simulated data series. The data indicate that, at frequencies up to every 60 min, all 3 programs are equal in their ability to detect true pulses of LH and FAS. However, the modified Santen & Bardin and Cluster (2 x 2) programs appear better in analyzing pulsatile glycoprotein hormone secretion at faster frequencies than Cluster (2 x 1) or Ultra. The higher false positive rate associated with Ultra may be explained by the fact that pulse detection is influenced significantly by the shape and frequency of the pulse signal and, while Ultra has been validated for analyzing growth hormone, ACTH and cortisol pulses (74, 75), it has not been validated for gonadotropin pulses.
In conclusion, we have shown that desensitization of FAS occurs at fast frequencies of GnRH stimulation in the human. Despite this observation, FAS is superior to LH as a marker of GnRH pulse generator activity at fast frequencies, presumably due to its shorter half-life.
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Acknowledgments |
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Footnotes |
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Received October 23, 1998.
Revised December 30, 1998.
Accepted January 5, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-subunit in man. J Clin Endocrinol Metab. 60:344–348.-subunit as an
alternative neuroendocrine marker of gonadotropin-releasing hormone
(GnRH) stimulation of the gonadotrope: evidence from normal and
GnRH-deficient men. J Clin Endocrinol Metab. 70:1654–1661.-subunit in postmenopausal
women. Clin Endocrinol. 34:477–483.[Medline]
-subunit secretion in post-menopausal women. Clin Endocrinol. 36:559–564.[Medline]
-subunit during gonadotropin releasing hormone agonist-induced
pituitary desensitization. J Clin Endocrinol
Metab.72:711–717.
-subunit secretion mirrors luteinizing hormone and
follicle-stimulating hormone in perifused rat pituitary cells. Endocrinology. 127:2364–2371.-subunit after gonadotropin-releasing
hormone and of TSH, LH ß- and -subunit after thyrotropin-releasing
hormone. J Clin Endocrinol Metab. 41:466–470.-subunit secretion. J Clin Endocrinol Metab. 62:102–108.-Subunit secretion in
men with idiopathic hypogonadotropic hypogonadism. J Clin
Endocrinol Metab. 66:338–342.-subunit from the gonadotrope
by gonadotropin-releasing hormone (GnRH): evidence from the use of two
GnRH antagonists. J Clin Endocrinol Metab. 70:328–335.-subunit (FAS) of
glycoprotein secreting hormones as a surrogate marker of GnRH secretion
in the human. In: Lustbader JW, Puett D, Ruddon RW, eds. Glycoprotein
Hormones, Structure, Function and Clinical Implications. New York:
Springer-Verlag; 253–263.
-Carboxymethylmercaptotestosterone-bovine serum albumin
conjugate. Measurement of testosterone in male plasma without
chromatography. Steroids. 28:101–109.[CrossRef][Medline]
-subunit in males with isolated gonadotropin-releasing hormone
deficiency. A clinical research center study. J Clin Endocrinol
Metab. 80:3682–3688.[Abstract]
-subunit levels during pulsatile
gonadotropin-releasing hormone replacement in women with idiopathic
hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 83:241–247.This article has been cited by other articles:
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J. M. Adams, A. E. Taylor, W. F. Crowley Jr., and J. E. Hall Polycystic Ovarian Morphology with Regular Ovulatory Cycles: Insights into the Pathophysiology of Polycystic Ovarian Syndrome J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4343 - 4350. [Abstract] [Full Text] [PDF]
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A. U. Meysing, H. Kanasaki, G. Y. Bedecarrats, J. S. Acierno Jr., P. M. Conn, K. A. Martin, S. B. Seminara, J. E. Hall, W. F. Crowley Jr., and U. B. Kaiser GNRHR Mutations in a Woman with Idiopathic Hypogonadotropic Hypogonadism Highlight the Differential Sensitivity of Luteinizing Hormone and Follicle-Stimulating Hormone to Gonadotropin-Releasing Hormone J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3189 - 3198. [Abstract] [Full Text] [PDF]
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C. K. Welt, Y. L. Pagan, P. C. Smith, K. B. Rado, and J. E. Hall Control of Follicle-Stimulating Hormone by Estradiol and the Inhibins: Critical Role of Estradiol at the Hypothalamus during the Luteal-Follicular Transition J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1766 - 1771. [Abstract] [Full Text] [PDF]
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C. K. Welt, A. E. Taylor, K. A. Martin, and J. E. Hall Serum Inhibin B in Polycystic Ovary Syndrome: Regulation by Insulin and Luteinizing Hormone J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5559 - 5565. [Abstract] [Full Text] [PDF]
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S. Gill, H. B. Lavoie, Y. Bo-Abbas, and J. E. Hall Negative Feedback Effects of Gonadal Steroids Are Preserved with Aging in Postmenopausal Women J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2297 - 2302. [Abstract] [Full Text] [PDF]
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F. J. Hayes, N. Pitteloud, S. DeCruz, W. F. Crowley Jr., and P. A. Boepple Importance of Inhibin B in the Regulation of FSH Secretion in the Human Male J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5541 - 5546. [Abstract] [Full Text] [PDF]
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 R. B. Perkins, J. E. Hall, and K. A. Martin Aetiology, previous menstrual function and patterns of neuro-endocrine disturbance as prognostic indicators in hypothalamic amenorrhoea Hum. Reprod., October 1, 2001; 16(10): 2198 - 2205. [Abstract] [Full Text] [PDF]
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S. Gill, A. E. Taylor, K. A. Martin, C. K. Welt, J. M. Adams, and J. E. Hall Specific Factors Predict the Response to Pulsatile Gonadotropin-Releasing Hormone Therapy in Polycystic Ovarian Syndrome J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2428 - 2436. [Abstract] [Full Text] [PDF]
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N. Pitteloud, P. A. Boepple, S. DeCruz, S. B. Valkenburgh, W. F. Crowley Jr., and F. J. Hayes The Fertile Eunuch Variant of Idiopathic Hypogonadotropic Hypogonadism: Spontaneous Reversal Associated with a Homozygous Mutation in the Gonadotropin-Releasing Hormone Receptor J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2470 - 2475. [Abstract] [Full Text] [PDF]
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L. M. B. Oliveira, S. B. Seminara, M. Beranova, F. J. Hayes, S. B. Valkenburgh, E. Schipani, E. M. F. Costa, A. C. Latronico, W. F. Crowley Jr., and M. Vallejo The Importance of Autosomal Genes in Kallmann Syndrome: Genotype-Phenotype Correlations and Neuroendocrine Characteristics J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1532 - 1538. [Abstract] [Full Text]
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M.-L. Kottler, S. Chauvin, N. Lahlou, C. E. Harris, C. J. Johnston, J.-P. Lagarde, P. Bouchard, N. R. Farid, and R. Counis A New Compound Heterozygous Mutation of the Gonadotropin-Releasing Hormone Receptor (L314X, Q106R) in a Woman with Complete Hypogonadotropic Hypogonadism: Chronic Estrogen Administration Amplifies the Gonadotropin Defect J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3002 - 3008. [Abstract] [Full Text]
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F. J. Hayes, S. B. Seminara, S. DeCruz, P. A. Boepple, and W. F. Crowley Jr. Aromatase Inhibition in the Human Male Reveals a Hypothalamic Site of Estrogen Feedback J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3027 - 3035. [Abstract] [Full Text]
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J. E. Hall, H. B. Lavoie, E. E. Marsh, and K. A. Martin Decrease in Gonadotropin-Releasing Hormone (GnRH) Pulse Frequency with Aging in Postmenopausal Women J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 1794 - 1800. [Abstract] [Full Text]
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