Vol. 276, Issue 1, R219-R225, January 1999
Evaluation of LH secretory dynamics during the rat proestrous
LH surge
Kathleen M.
Hoeger1,
Lisa A.
Kolp2,
Frank J.
Strobl3, and
Johannes D.
Veldhuis2,4,5
1 Department of Obstetrics and
Gynecology, Division of Reproductive Endocrinology, University of
Rochester School of Medicine and Dentistry, Rochester, New York
14642; 2 Departments of Obstetrics and
Gynecology and 4 Internal
Medicine, 5 National Science
Foundation Center for Biological Timing, University of Virginia Health
Sciences Center, Charlottesville, Virginia 22908; and
3 Department of Pathology and
Laboratory Medicine, University of Wisconsin Hospital and Clinics,
Madison, Wisconsin 53792
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ABSTRACT |
The
preovulatory luteinizing hormone (LH) surge results from the
integration of complex interactions among gonadal steroids and
hypothalamic and pituitary hormones. To evaluate changes in LH
secretory dynamics that occur during the rat LH surge, we have 1) obtained frequently sampled serum
LH concentration time series, 2)
used both waveform-dependent and waveform-independent convolution analyses, and 3) independently
assessed proestrous LH half-life and basal
non-gonadotropin-releasing hormone (GnRH)-dependent LH
secretion during the LH surge. Waveform-independent pulse analysis revealed a 24-fold increase in the maximal pulsatile LH secretory rate
attained during late proestrus compared with early proestrus. A 15-fold
increase was quantified for the mean LH secretory rate. In
complementary analyses, we applied a measured LH half-life of 17 ± 2.7 min and a median basal LH secretion rate of 0.0046 µg · l
1 · min1 for convolution
analysis, revealing a 16-fold increase in the mass of LH released/burst
and more than sixfold rise in the amplitude of the secretory peaks.
Evaluation of the approximate entropy of the LH surge profiles was
performed, showing an increase in the orderliness of the LH release
process during the surge. We conclude that both quantitative
(mass/burst) and qualitative (approximate entropy) features of LH
release are regulated during the proestrous LH surge.
deconvolution; pulse analysis; rat luteinizing hormone half-life; approximate entropy
| |
INTRODUCTION |
THE PREOVULATORY LUTEINIZING HORMONE (LH) surge
represents the culmination of a complex interplay of gonadal steroid,
hypothalamic, and pituitary hormones. The precise neuroendocrine
mechanisms that subserve this massive increase in serum LH are still
not well described. Early analysis of the proestrous LH surge focused on characterizing changes in serum LH concentrations and the rate of
rise of blood LH levels (1, 2). Further investigations demonstrated that the release of LH in peripheral blood during the
preovulatory LH surge remained significantly pulsatile in the rat (5)
and monkey (15, 22). The surgelike rise and fall in serum LH
concentrations in the sheep seemed to be accounted for by changes in
both LH pulse amplitude and frequency (8, 13). The pulsatile release
patterns of LH in diestrous and immediately proestrous rats were
comparable just before the surge, but the latter abruptly increased
during the surge (4). Mechanistically, the massive increase in serum LH
concentrations might be explained by increases in LH secretory burst
mass and/or frequency, a prolongation of the effective blood
half-life of LH, and/or an increase in gonadotropin-releasing
hormone (GnRH)-independent (tonic or basal) LH release. The possible
contributions of these factors individually and jointly cannot be
adequately assessed using conventional pulse analysis, because blood LH
concentrations result from the so-called convolved or combined effects
of these dynamics (7, 27). A single prior deconvolution analysis of the
rat spontaneous proestrous LH surge has been reported using a
model-based multiparameter approach to attempt to simultaneously
characterize four distinct parameters: the number of secretory bursts,
their amplitudes and duration, basal LH secretion, and LH half-life
(29). However, this is technically very challenging given the highly
correlated nature of the principal measures of interest, namely LH
secretory burst amplitude, basal LH secretion rate, and LH half-life
(3, 23, 24, 29). Solutions to this technical impasse require independent knowledge of the LH half-life and basal LH secretion rate
(7, 25, 27, 28). Alternatively, model-independent calculations of
sample LH secretory rates would be valuable to complement an assumed
secretory model structure of approximately Gaussian secretory bursts
(24). In addition, the regularity or orderliness of LH release can be
now assessed via a model-free and translation- and scale-invariant
statistic, approximate entropy (ApEn; 6, 16, 17), which should allow
insights into the temporal organization of the LH release process
during the surge mode of gonadotropin secretion. To these ends, we have
reinvestigated the dynamic neuroendocrine mechanisms underlying the rat
preovulatory LH surge by 1)
independently assessing the LH half-life and GnRH-independent LH
release, 2) applying both
waveform-independent and -dependent analyses, and
3) estimating the ApEn of LH release
on the (first differenced) LH data.
| |
METHODS |
Animals.
Adult female Sprague-Dawley rats (Charles River Laboratories,
Wilmington, MA) weighing 200-250 g were used. Animals were housed with a 14:10-h light-dark cycle (lights on 0500). This reliably produces an LH surge in the early afternoon of proestrus. Rat chow and
water were given ad libitum. Vaginal smears were recorded daily, and
only rats showing at least two consecutive 4-day estrous cycles were
used. Daily vaginal smears were continued through at least one estrous
cycle after the blood sampling procedure to evaluate sampling effect on
cycling or, alternatively, animals were killed to evaluate ovulation
the day after sampling. In the experiments involving determination of
LH half-life, proestrous rats were used as the source of LH and
hypophysectomized rats were used as recipients of injected LH serum. At
least 10 days elapsed posthypophysectomy before the animals were used
in the protocol.
In the experiments evaluating LH secretion after suppression of GnRH
release or action, two methods of suppression were studied. Initial
suppression of GnRH was performed using intraperitoneal pentobarbital
sodium, which has been shown to reliably suppress the LH surge (2). The
GnRH antagonist antide was then used for its simplicity and direct
action when this compound was available. In
group
A, animals were injected
intraperitoneally (n = 2) with pentobarbital sodium (40 mg/kg) at 1330 on proestrus. In
group B, animals
(n = 3) were injected subcutaneously
with GnRH antagonist Antide (Sigma Chemical;
[N-Ac-D-2-Nal1,D-4-Cl-Phe2,D-3-Pal3,Nic-Lys5,D-Nic-Lys6,L-Lys8,D-Ala10]GnRH)
in doses of 20 or 800 µg/kg in corn oil at 1200 on proestrus. In an
independent evaluation, antide doses were reliably shown to inhibit LH
release (data not shown). To examine pituitary responsiveness to a GnRH
bolus after the sampling, 1,000 ng of GnRH (in 1.0 ml PBS) was injected
intravenously at the conclusion of sampling (described below) and blood
samples were withdrawn 20 and 30 min for later LH determinations. The
two modes of treatment resulted in similar suppression of LH release.
For the purposes of statistical evaluation, both groups were combined
in the determination of median GnRH-independent LH release. All
experiments were approved by the Institutional Animal Care and Use
Committee at the University of Virginia.
Blood sampling procedure.
Blood sampling was performed and bolus injections were made via a
Silastic catheter in the right external jugular vein, which was placed
under metafane anesthesia at least 24 h preceding the sampling time.
Animals were housed separately after the catheter placement under
similar conditions in the animal facility. The catheter did not
restrict the animal's mobility. Sampling was performed the afternoon
of proestrus either from 1200 to 1800 (early proestrus,
n = 6) or from 1530 to 2030 (late
proestrus, n = 7). Blood
(500 µl) was withdrawn every 5 min and replaced by washed red blood
cells resuspended in plasmanate (hematocrit 54%) plus 0.2 ml
heparinized saline (50 IU/ml, catheter volume) in a volume equal to
that removed. Replacement blood was prepared via a previously described
protocol (21). Animals were carefully observed for alteration in normal
behavior during the entire sampling period, with food and water
available as wanted.
To evaluate LH half-life, serum from proestrous rats was collected at
1700 via cardiac puncture. Serum (vol 2 ml) was injected into
hypophysectomized rats (n = 5) via a
jugular catheter with samples taken at 0, 1, 3, 5, 7, 12, 30, and 60 min. Blood samples were stored overnight at 4°C, and the serum was
separated the following morning and stored at 
20°C until
hormone analysis. Results of four LH decay curves are displayed in Fig.
1.
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Fig. 1.
Luteinizing hormone (LH) decay curves from 4 hypophysectomized rats
injected with serum from proestrous rats collected at time of LH
surge.
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Hormone analysis.
Serum samples for LH were analyzed in duplicate by a double-antibody
radioimmunoassay. First antibody for LH was National Institute of
Diabetes and Digestive and Kidney Diseases anti-rabbit LH-S-11, and hormone levels were expressed in terms of rat
LH-RP-3(AFP-7187B) standard for LH. Purified hormone,
iodinated with 125I by the
chloramine-T method, was supplied by Hazelton Laboratories, Vienna, VA.
The second antibody was a goat anti-rabbit antibody supplied by
Henniger Laboratories. This LH assay has a sensitivity of 0.1 ng/ml for
a 100-µl sample, an intra-assay coefficient of variation of
1.2-12.2% (mean 6.8%), and an interassay coefficient of
variation of 11%. For deconvolution analyses, LH duplicate variances
within any given series were fit as a power function of LH dose (23).
Data analysis. Serum LH concentration
versus time series were generated for all rats sampled. LH half-life
data in the hypophysectomized rats (n = 5) were analyzed by exponential curve fitting as previously described
(14, 26, 28) using single component LH elimination kinetics. The mean
half-life, 17 ± 2.7 (±SE) min, was used in subsequent
model-free deconvolution analysis of frequently sampled LH
concentration time series in the proestrous rat. A GnRH-independent (time invariant) LH secretion rate was computed from LH concentration time series in rats (n = 5) treated
with pentobarbital sodium (n = 2) or
antide (n = 3). The median calculated
basal LH secretion rate of 0.0046 µg · l1 · min1,
corresponding to a median basal serum LH concentration of 0.113 µg/l,
was used in both the model-specific and model-free deconvolution analyses of the LH concentration time series in the proestrous rats.
Initial deconvolution-based evaluation of LH concentration time series
was performed using waveform-independent (model free) analysis. Sample
secretion rates were calculated using the PULSE2 program developed by
Johnson and Veldhuis (7). This algorithm provides an automated method
for calculating all sample secretion rates without assumptions
concerning the number or shape of the secretory bursts and/or
the presence or absence of basal secretion. Program parameters were
defined to include fixed values of the proestrous LH half-life as
determined directly (above) and GnRH-independent (basal) LH secretion
rate (above). Secretion rates are reported as median as well as mean ± SE values, and histograms of sample secretion rates were generated.
A waveform-specific (Gaussian) model of burstlike hormone secretion
(26-28) also was applied. Significant secretory bursts were
identifiable at P < 0.01 on the
assumption of fixed a priori values of the LH half-life and basal
secretion rates determined above (14, 26, 28).
ApEn was calculated for m = 1 (window
size or vector length) and r = 0.2 SD
(filter or threshold) after first differencing of the LH data to remove
nonstationarity (6, 16, 17). ApEn was also calculated for the PULSE2
secretion profiles, because such calculated values are detrended by
deconvolution (28). Larger ApEn values denote relatively greater
irregularity or disorderliness of serial hormone measures, information
that is complementary to pulse analysis (above).
Statistical analysis. Because of
significant departures from normality for some of the calculated
secretory parameters in the deconvolution analysis, nonparametric
testing (Wilcoxon's unpaired rank sum two-tailed test) was used to
compare measures in the early proestrous and surge profiles. The
unpaired Student's two-tailed t-test
was used for comparison of maximal LH secretory rates, mean serum LH
concentrations, and integrated areas under the serum LH concentration
versus time curves. One-way ANOVA was used to compare the mean ApEn of
the suppressed, early proestrous, and surge profiles.
P values <0.05 were construed as
significant. Data are given as median and means ± SE.
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RESULTS |
Figure 2 presents a composite histogram of
sample LH secretion rates calculated by waveform-independent
deconvolution analysis of six early proestrous control rats (Fig. 2,
top), seven proestrous rats sampled
during the LH surge (Fig. 2,
middle), and five GnRH-suppressed rats (Fig. 2, bottom). A comparison
of the LH secretory rates in early proestrus and during the
preovulatory surge is presented in Table 1.
The maximal LH secretory rate in the early part of proestrus was 0.21 ± 0.27 µg · l1 · min1,
whereas the maximal rate during the proestrous surge was found to be
5.1 ± 0.41 µg · l1 · min1,
a 24-fold increase. Correspondingly, a 15-fold increase in the mean LH
secretory rate was observed between early proestrus and preovulatory LH
surge.
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Fig. 2.
Composite histograms of waveform-independent calculated LH secretion
rates in 6 early proestrous (top), 7 surging (middle), and 5 gonadotropin-releasing hormone-suppressed (GnRH;
bottom) rats.
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Table 1.
Comparison of sample LH secretory rates estimated by
waveform-independent deconvolution analysis between early
proestrous and preovulatory surge profiles
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The results of the multiple-parameter deconvolution (Gaussian)
waveform-specific analysis of the proestrous surge and early proestrus
are presented in Fig. 3 and Table
2. Figure 3,
left, shows six representative LH
surge profiles from rats sampled in late proestrus, and Fig. 3,
right, illustrates six other profiles from the early proestrus. A matching set of plots represents the calculated LH secretory rates. Statistical analysis revealed no significant changes in half-duration but showed an increase in the
number of bursts per hour, a 16-fold increase in the mass of LH
released per burst, and a more than sixfold rise in the amplitude of
the secretory peaks. Collectively these changes represented an LH
production rate increase of 25-fold during the LH surge.
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Fig. 3.
Individual model-based (multiple parameter) deconvolution analyses of
LH concentration-time series during the surge
(left) and early proestrus
(right).
A: fitted serum LH concentration
values over time. B: calculated
(predicted) LH secretory rates in the same animals. Note different
scales on y-axes to accommodate a
variable range of observation among animals. One surge profile, which
was selected by random assignment, is not shown.
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Table 2.
Waveform-specific deconvolution analysis of LH secretion and
clearance parameters in early proestrous and preovulatory surge
profiles
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Table 3 presents the ApEn values for the LH
surge profiles, early proestrous profiles, and the LH suppressed
profiles. LH release profiles during early proestrus and in the
suppressed state were comparable in quantifiable regularity or
orderliness. However there was a significantly greater orderliness
during the LH surge itself (significantly lower ApEn;
P = 0.024 by ANOVA).
| |
DISCUSSION |
In this study we have reevaluated the temporal mechanisms subserving
the massive increase in serum LH concentrations during the preovulatory
LH surge by using for the first time both waveform-independent and
waveform-specific (multiple parameter) deconvolution analyses. Deconvolution analysis allows one to compute the number, amplitude, duration, and mass of LH secretory bursts, but the simultaneous calculation of LH half-life and basal LH secretion is technically challenging given the highly correlated nature of these parameters (25). Therefore, in the present investigation, we independently assessed the parameters of LH half-life and basal non-GnRH-dependent LH
release. These estimates then were applied to analysis of the proestrous LH surge. Waveform-independent (PULSE2) analysis
demonstrated a massive increase in the maximal pulsatile LH secretory
rate, namely by 24-fold, during the LH surge. The mean LH secretion rate also rose ~16-fold. As a complementary analytic tool,
model-specific (Gaussian waveform) deconvolution analysis revealed an
increase in the number of secretory bursts per hour of 1.8-fold and an increase in the mass of LH released per burst of 16-fold (with a
6.7-fold rise in the amplitude of calculated LH secretory bursts). This
resulted in a 25-fold increase in the pulsatile production rate of LH
during the surge. Thus both approaches disclosed similar (24-25
fold) augmentation of pulsatile LH secretion. These changes could be
adequately modeled without invoking an increase in the tonic (non-GnRH
dependent) secretion of LH or any prolongation of LH half-life.
A single prior deconvolution analysis of the rat proestrous surge,
using model-based computer-assisted estimates of LH half-life and tonic
non-GnRH dependent LH release, suggested that the massive rise in LH
concentrations during the surge might be accounted for, at least
mathematically, by multiple mechanisms, including 1) an increase in the frequency,
amplitude, and duration (and/or mass) of LH secreted per pulse,
2) a rise in tonic LH secretion, and
3) a prolongation of LH half-life
(29). In the present work, we used additional information in the form
of an experimentally derived LH half-life and estimates of
non-GnRH-dependent (basal) LH release rates. Given such data, the LH
surge in the rat could be adequately modeled without a rise in
nonpulsatile LH secretion or a change in LH half-life. Indeed, the
amount of basal LH release that we estimated would be expected to be a
maximal non-GnRH-dependent contribution to LH release during the surge.
We have not attempted to quantitate by deconvolution techniques any
(putative) GnRH-independent interpulse basal LH release in view of
confounding by highly correlated variables [e.g., between
simultaneously fitted basal secretion rates and pulse mass (25)].
Rather, we have directly estimated, by GnRH-suppression experiments,
residual (non-GnRH dependent) basal LH secretion.
Assessment of the degree of irregularity of secretion or its
"orderliness" may reflect the temporal organization and
efficiency of the secretory process over time. Quantification of
regularity of hormone release has been accomplished recently via the
ApEn statistic (6, 16, 17). This concept has been applied to the
evaluation of LH and testosterone secretion in men with evidence that
aging of the hypothalamic-pituitary axis results in greater irregularity of LH and androgen secretion (17). The possible utility of
this calculation arises from putative boundary or transitional states,
wherein changes in the orderliness of pulsatile hormone release may
mark the onset of pathophysiology. ApEn is a novel statistic that is
complementary to PULSE analysis because it detects subordinate patterns
in the data. In particular, ApEn is sensitive to short-term variation
rather than epochs. ApEn measures the likelihood that runs of patterns
that are close remain close on the next incremental comparison (16). In
the present experiments, we evaluated ApEn in (detrended) LH time
series preceding and during the surge, as well as in the LH-suppressed
state. Our finding of no ApEn differences in the orderliness of LH
secretion between early proestrus and the GnRH-suppressed state but
greater orderliness during the LH surge indicates that the serial
regularity or orderliness of LH release is actually enhanced during the
LH surge. In contrast, the orderliness of neurohormone release is
disrupted by aging (17) and various tumoral states (6). Increased
orderliness likely reflects enhanced coordination among LH release
processes during the surge.
This study was not intended to quantitate the amplitude or frequency of
hypothalamic GnRH release episodes at the time of the LH surge. Other
studies have shown significant increases in the amount of GnRH secreted
by the hypothalamus and significant increases in hypothalamic multiunit
electrical activity during the surge in various species (2, 9, 13, 20).
Whether both the amplitude and frequency of GnRH release rise in all
species at proestrus is not entirely clear. Prior studies in primates have demonstrated that fixed doses of GnRH infused at regular intervals
will induce an LH surge in hypothalamopituitary-disconnected animals,
suggesting that significantly enhanced pituitary sensitivity to GnRH is
also physiologically relevant at the time of an LH surge (10).
Experience with GnRH infusion in humans with isolated GnRH deficiency
also corroborates this finding (19). Estrogen treatment of
postmenopausal women amplifies pituitary responsiveness to exogenous
GnRH by augmenting GnRH efficiency (rather than potency) (18).
Furthermore, there is evident GnRH dependency of the
progesterone-induced surgelike release of LH in the estrogen-primed
postmenopausal woman, as inferred by the ability of pretreatment with a
potent GnRH antagonist to abolish the otherwise consistent increase in LH release (11). The present results in the rat show suppression of the
proestrous LH surge by a different GnRH antagonist administered immediately before the anticipated LH surge, lending support to the
GnRH dependency of the preponderance of LH release within this interval
of the spontaneous proestrous surge.
In summary, we have demonstrated that the massive increase in serum LH
concentrations that occurs during the rat proestrous LH surge can be
accounted for by a 24- to 25-fold increase in the maximal pulsatile LH
secretory rate, which by deconvolution analysis is shown to be a result
of a 1.9-fold increase in burst frequency and a 16-fold increase in the
mass of LH released per burst. These contributing mechanisms can
adequately account for the amount of LH released during the surge
without invoking a change in the LH half-life or an increase in
non-GnRH-dependent LH release. Moreover, the quantifiable regularity of
LH release is enhanced during the surge (as estimated by an approximate
entropy statistic), indicating an amplification of coordinated LH secretion.
Perspectives
The preovulatory proestrus LH surge, a key event in the estrous cycle,
has been the subject of much prior investigation. Although much has
been learned about the influence of GnRH and the release of LH, the
precise neuroendocrine mechanisms underlying the massive increase in
serum LH have not been well described. We have shown that the increase
in serum LH can be explained by a 25-fold increase in the production
rate of LH, which appears to be dependent on the input of GnRH. In
addition, the orderliness of LH release is enhanced during the surge.
With respect to disease states, both an abnormal amount of LH
production and an increase in disorder in secretion can be potential
sources for reproductive abnormalities. A clear understanding of the
normal processes that subserve the complex interactions of gonadal
steroids and hypothalamic and pituitary hormones that define the
preovulatory LH surge is important to our understanding of disease
processes. This current work serves to better define the normal process
in a single species. Additional work should be undertaken to understand
these processes in other species. Furthermore, elucidation of the
precise role of GnRH in facilitating the LH surge with regards to
enhanced pituitary sensitivity or an increase in the amount of GnRH
released as well as the underlying neuroendocrine control mechanisms is needed.
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ACKNOWLEDGEMENTS |
We thank Paula P. Azimi for assistance in data analysis and
skillful preparation of the artwork.
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FOOTNOTES |
This work was supported in part by National Institutes of Health (NIH)
P-30 Center for Reproduction Research at the University of Virginia
(HD-28934), National Institute of Child Health and Human Development
(NICHD) Research Career Development Award IK04-HD00634 (to J. D. Veldhuis), NICHD Clinical Investigator Award K08-HD00943 (to L. A. Kolp), and the National Science Foundation Center for Biological Timing
(to J. D. Veldhuis).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: K. Hoeger, Dept of Obstetrics and
Gynecology, Univ. of Rochester School of Medicine and Dentistry, 601 Elmwood Ave. Box 668, Rochester, NY 14642.
Received 13 April 1998; accepted in final form 29 September 1998.
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Abstract
Introduction
