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Reproductive Sciences Program (V.P., K.M., F.J.K., A.R.M.) and the Departments of Pediatrics (V.P.), Physiology (F.J.K.), and Biostatistics (D.T.M.), University of Michigan, Ann Arbor, Michigan 48109-0404
Address all correspondence and requests for reprints to: Dr. Vasantha Padmanabhan, Reproductive Sciences Program, 300 North Ingalls Building, Room 1101, Ann Arbor, Michigan 48109-0404. E-mail vasantha{at}umich.edu
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Abstract |
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Introduction |
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Although several laboratories, including ours, have attempted to characterize the pulsatile release of immunoreactive FSH from peripheral measurements in sheep and other species, such assessments have often (7, 8, 9, 10) not yielded a convincing answer to a simple but fundamental question: is FSH secretion episodic? The utilization of a surgical approach, which was originally established to characterize secretory patterns of hypothalamic hormones (11), to define secretory dynamics of pituitary hormones (12) has provided us with a unique approach to address this question definitively. The approach exploits the hypophyseal portal blood collection technology (11, 13). Because hypophyseal portal vessels are cut at the level of the pituitary, we postulated that hypophyseal portal blood would serve as a suitable medium for determining the secretory dynamics of pituitary secretions. This premise proved to be true for LH (12). Capitalizing on this approach, we here provide direct evidence that FSH secretion in ovariectomized ewes is indeed comprised of both episodic and basal components of release. Furthermore, the episodic mode of FSH secretion appears to be comprised of both GnRH-associated and non-GnRH-associated pulses of secretion.
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Materials and Methods |
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All procedures were approved by the University Committee on the Use and Care of Animals.
RIAs
Hypophyseal portal and jugular FSH were assayed in duplicate by
a previously validated RIA (15, 16, 17). The assay uses the 620 antibody at
a 1:48,000 dilution (17) and purified ovine FSH (NIDDK oFSH-1) for
iodination as well as a reference standard. All samples from each
animal were measured in a single assay. The assay sensitivity (2 SD
from the buffer control) averaged 3 pg/tube (range, 2–5 pg). The
cross-reactivity of the 
-subunit averaged less than 0.3%. Intra-
and interassay coefficients of variation based on three quality control
pools at approximately 0.9, 1.7, and 6.0 ng/ml averaged less than
12%.
To minimize degradation of GnRH during collection and to chill hypophyseal portal samples in an ice bath as quickly as possible, the collection rate was set at a higher speed than the rate of flow of hypophyseal portal blood into the collection apparatus (13). This led to the collection of hypophyseal portal blood as discrete blocks segmented by air; this approach minimized dispersion of secreted products during collection. Jugular blood, on the other hand, was collected as a continuous stream in the collection line. To allow direct comparisons with concentrations of FSH in peripheral samples (nanograms per ml), all measurements of FSH (as well as LH and GnRH) in hypophyseal portal plasma are reported as concentrations. Furthermore, to adjust for the difference in transit time in the collection line (10–12 min for jugular blood and 3 min for hypophyseal portal blood), samples are offset by 10 min (two samples) for the purpose of plotting. It should be noted that a small error of 1–3 min may remain.
Statistical analysis
The measured concentration of hormone in the hypophyseal portal
blood is the sum of that which is secreted plus that which
recirculates. To obtain an estimate of secreted FSH, the concentration
of FSH in each jugular sample was subtracted from that in the
corresponding hypophyseal portal sample. Although subtracting the
jugular concentrations adds another, small source of error to the
portal data, the variation in jugular concentrations is so much smaller
than changes in hypophyseal portal circulation that subtracting the
jugular values is for all practical purposes like subtracting a small
constant. All hormonal series from each ewe were analyzed with the
Kushler-Brown Pulsefit algorithm (18). This statistical model is
nonlinear, assumes exponential decay, and attempts to account for the
error in measurements due to biological noise as well as assay error.
Pulses are identified by stepwise selection. As the algorithm is
limited to identifying pulses that are no longer than two observations
on the upslope, a postprocessor merges pulses that are contiguous in
time into a single pulse. Concordant pulses of GnRH and FSH, LH and
FSH, and hypophyseal portal FSH and jugular FSH were identified; pulses
beginning within 10 min (two samples) of each other were considered to
be concordant. The average lag time between concordant pulses was also
estimated for each ewe. In addition, to assess the overall temporal
relationships between hormone patterns, the cross-correlation for the
above variables was calculated at different time lags
(autocross-correlation). The time lag that yields the highest
cross-correlation is an estimate of the overall time lag between two
series. The average pulse lag time simply estimates the temporal
relationship between concordant pulsatile episodes. Within-animal
comparisons, such as amplitude of GnRH-associated vs.
non-GnRH-associated pulses, were performed using paired t
tests or the nonparametric Wilcoxon signed rank test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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depicts representative patterns of
hypophyseal portal (top panel) and peripheral FSH in two
ovariectomized ewes sampled during the anestrous season (ewe 5 and
6 h in ewe 3). Levels are plotted on the same scale to provide an
estimate of the magnitude of differences between the peripheral and
hypophyseal portal levels. For comparison, previously reported
hypophyseal portal and jugular patterns of LH (14) are shown in the
bottom panel. Concentrations of FSH in hypophyseal portal
blood were several-fold higher than those in the peripheral
circulation. FSH patterns in hypophyseal portal blood showed a
distinctively episodic pattern of release that appeared to be
superimposed over a basal level of secretion. The relative increases in
FSH secretory episodes appeared to be lower in magnitude for FSH than
LH. Furthermore, the magnitude of changes occurring between FSH in
portal and jugular circulations often did not parallel the changes
occurring between hypophyseal portal and jugular LH, even within a
given sample.
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shows patterns of hypophyseal portal
(closed circles) and jugular FSH (open circles)
in two other ewes sampled during the breeding season (ewes 1 and 2).
Also shown are corresponding, previously reported patterns of
hypophyseal portal and jugular LH (lower panel) and GnRH
(shaded patterns in both panels). Comparison of time courses
of GnRH, LH, and FSH revealed that, although the dominant patterns of
GnRH and LH were pulsatile, the pattern of FSH was comprised of both
pulsatile and basal components. In contrast to the absolute one to one
relationship of LH to GnRH (12, 14), not all episodes of FSH release
were associated with a detectable GnRH pulse. Episodes of FSH secretory
activity were evident between GnRH-associated pulses of FSH. In several
instances (identified by arrows in Fig. 2), GnRH-associated
bursts of FSH appeared to develop upon a previously triggered episode
of FSH release.
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and 4 summarize the patterns of
secreted (see Materials and Methods for calculation) and
jugular FSH from two ovariectomized ewes. To reveal more clearly the
comparative magnitude of changes in the hypophyseal portal and
peripheral blood and to account for heterogeneity of variance, values
are plotted on a logarithmic scale. To provide an estimate of
measurement errors, the range of duplicate values is also shown (the
thin lines running on either side of the plotted
concentrations of secreted FSH). Previously reported patterns of GnRH
(14) are coplotted to facilitate comparisons. As reported previously
(14), GnRH was released in discrete episodes, between which values
returned to an undetectable or nearly undetectable baseline. Each pulse
of GnRH was directly associated with a concomitant episodic burst of
FSH in hypophyseal portal plasma. In contrast, such an association was
not evident between GnRH and jugular FSH. FSH remained elevated between
episodes of release, whether measured at the hypophyseal portal or
jugular levels. The interval between the onset of the GnRH burst and
secreted FSH in the hypophyseal portal blood was very short, with
initial increases occurring within the same 5-min sample for both
hormones. The subsequent fall in secreted FSH was rapid, but slower
than that for GnRH.
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. Shown in Table 1A for each ewe are the sampling
duration, number of portal and jugular FSH pulses identified, and
number of pulses per h. Previously reported pulse numbers of GnRH from
the same ewes (14) are provided in parenthesis for
comparison. Within each series, although the number of LH pulses
identified in the hypophyseal portal plasma was the same as the number
identified for GnRH (12), the number of FSH pulses identified in the
hypophyseal portal plasma far exceeded that for GnRH. The mean pulse
amplitude of hypophyseal portal FSH is shown in Table 1B. Portal FSH
pulses were 18.0 ± 5.5-fold greater in amplitude than jugular FSH
pulses. Further, GnRH-associated pulses of FSH were larger
(P < 0.01) than non-GnRH-associated pulses of FSH
(57.7 ± 10.8 vs. 43.4 ± 11.4 ng/ml,
respectively; Table 1C). Such a relationship was not evident when the
analysis was conducted on jugular FSH pulses (3.6 ± 0.8
vs. 3.2 ± 0.3). The disappearance time of FSH in the
hypophyseal portal plasma, although not as rapid as that reported for
GnRH (1.7 ± 0.2 min), was much faster than that observed for FSH
in the periphery (7.8 ± 2.3 vs. 26.2 ± 5.5 min
for hypophyseal portal and peripheral FSH, respectively; Table 1B).
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summarizes average concentrations of FSH in the
hypophyseal portal and peripheral circulations during the 6-h
collection period and the relative proportions of the basal and
episodic components. The total FSH level measured in hypophyseal portal
blood during the 6-h collection period was approximately 21-fold
greater than that measured in peripheral blood (2919.8 ± 1023.5
vs. 138.9 ± 38.2 ng/ml, respectively). Total FSH
measured in the basal compartment of FSH secretion during the 6-h
collection period averaged 2245.1 ± 897.0 and 101.5 ± 36.5
ng/ml in hypophyseal portal and jugular circulations, respectively.
Although basal GnRH concentrations were reported to be at or near the
limit of detection (14), the mean baseline of hypophyseal portal FSH
was 8.2 ± 2.4-fold greater than that estimated for peripheral FSH
(68.4 ± 16.6 vs. 9.1 ± 1.0 ng/ml, respectively).
A substantially greater proportion of FSH comprised the basal component
compared with the episodic component (72.9 ± 3.8% vs.
27.1 ± 3.8%, respectively; P < 0.01). A similar
relationship was noted for jugular FSH (69.2 ± 6.5%
vs. 30.8 ± 6.5%, respectively; P <
0.01).
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summarizes the pulse concordance relationships
of GnRH and FSH (solid bars), with values for GnRH and LH
provided for comparison in the background (striped bars). As
reported earlier, a virtual one to one relationship exists between GnRH
and LH, whether LH was measured at the hypophyseal portal (12) or
peripheral level (14). Similarly, assessment of FSH in hypophyseal
portal blood revealed a close association between GnRH and hypophyseal
portal FSH, with 93% of the GnRH pulses found to be associated with
FSH pulses. This relationship was less pronounced when GnRH and jugular
FSH pulses were compared (79% concordance). Episodes of FSH secretion
were identified in the absence of corresponding GnRH pulses (31.5% in
hypophyseal portal and 45% in peripheral blood).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Episodic mode of FSH secretion
Although part of the problem in assessing secretory dynamics of
FSH in the periphery has stemmed from its long half-life (22, 23, 24), it
has also been confounded by the molecular heterogeneity of FSH (25).
FSH isoforms secreted in pulses appear to have a much shorter half-life
compared with those secreted in between pulses (8, 26). Despite these
caveats, studies in rats have documented clearly discernible
episodic patterns of circulating FSH (27). However, because -subunit
is also secreted in a pulsatile manner (28), and cross-reactivity
in the FSH assay was not assessed, these studies did not discern
whether the observed pulsatility resulted primarily from episodic
secretion of FSH or pulsatile secretion of the -subunit. Studies in
sheep (7, 8) and humans (10) have failed to show discrete pulses of FSH
such as those seen for LH and have relied heavily on statistical
approaches to deconvolve pulses (29). Our own studies in nutritionally
growth-retarded ovariectomized lambs, in which GnRH secretion is
dependent on the nutritional status of the animal, have shown the
existence of bioactive, but not clearly definable (except by pulse
analysis), immunoreactive pulses of FSH (8). Supportive evidence for a
GnRH-driven episodic component of FSH has come from perifusion studies
(30, 31, 32) in which FSH secretion mirrors the delivered pulsatile pattern
of GnRH.
Using cavernous sinus sampling as an approach to get closer to the
secretion site, Irvine and Alexander (33) characterized the secretory
pattern of FSH during the luteal phase of the cycle in horses, a time
when GnRH pulse frequency is expected to be low. They identified eight
pulses of concurrent LH and FSH in both the pituitary and peripheral
blood during 80 h of sampling. Unfortunately, this study, similar
to those in rats, did not provide an estimate of the -subunit
cross-reactivity of the FSH assay. Using a well characterized FSH assay
(15, 16, 17) that cross-reacts minimally with -subunit (<0.3%) and a
unique approach for characterizing FSH secretion dynamics in
vivo, our studies extend the observations from the mare and
unequivocally demonstrate that an episodic component of FSH secretion
exists.
Key to our understanding of whether other hypothalamic factors regulate pulsatile control of FSH secretion is the determination of whether all identified pulses of FSH are concurrent with GnRH pulses. In contrast to studies in the mare (33), in which 35% of the identified GnRH pulses had no concurrent FSH or LH pulses, almost all (93%) of the GnRH pulses in this study were associated with FSH pulses. Such a close relationship was, however, not evident when FSH pulses were identified in the peripheral circulation. The very discrete nature of the GnRH-associated bursts of FSH in the hypophyseal portal blood and the close time lag relationship between GnRH and FSH suggest that the primary factor responsible for induction of the GnRH-associated pulses of FSH is GnRH.
Interestingly, secretory excursions of FSH were also identified in the absence of detectable GnRH pulses. Furthermore, many of the GnRH-associated pulses of FSH themselves appeared to develop on top of a previously elicited episode of FSH release. In forming a judgment regarding non GnRH-associated episodic FSH secretion, one should bear in mind that the blood passing from the hypophyseal-portal circulation is not returned; washout can lead to very fast disappearance times. Thus, simple persistence of concentrations is indicative of additional FSH release; the fact that the concentrations increase provides evidence for incremental active secretion. The existence of fairly discrete, non-GnRH-associated excursions of FSH suggests external coordination of the gland by some trigger, rather than independent activity within the pituitary gland. An understanding of what controls the non-GnRH-associated component of episodic FSH secretion is critical to our understanding of the control of the secretion of this hormone. Several possibilities are plausible. First, the non-GnRH-associated excursions of FSH could be the outcome of intrinsic pituitary FSH rhythmicity. This appears unlikely, because long term perifusion studies of dispersed ovine pituitary cells fail to show such an episodic pattern of secretion (our unpublished data). Second, non-GnRH-associated episodes of FSH secretion could represent FSH responses to low levels of GnRH (not detectable by RIA and subthreshold for LH). This also seems unlikely because dose-response studies carried out in static cultures (our unpublished data) and in nutritionally growth-restricted ovariectomized lambs (34) show FSH not to be more sensitive to GnRH. Furthermore, preliminary studies that used GnRH antagonists to block GnRH input in ovariectomized ewes show that such excursions in FSH persist even after complete blockade of GnRH action (35). Another possible explanation is that non-GnRH-associated release of FSH is caused by acute changes in locally produced inhibin, activin, and/or follistatin (36, 37, 38, 39, 40). This, however, seems unlikely in view of the findings that these FSH regulatory peptides take long to act and have a sustained effect on the basal FSH secretion (41, 42, 43), as opposed to the rather discrete FSH secretory episodes that were often observed in this study.
Another possibility is that the non-GnRH-associated episodes of FSH release are the outcome of inputs from a selective FSH-releasing-factor(s) originating from the hypothalamus. Studies demonstrating selective regulation of FSH release after ablation (44), deafferentation (45), or destruction (46) of the dorsal anterior hypothalamic area or electrochemical stimulation of hypothalamic regions apart from those that regulate LH secretion (47) strongly support a specific site of control for FSH release. Evidence supporting the existence of FSH-releasing factor was first provided by Igarashi and McCann (48). Although considerable anatomical and biochemical evidence supports this possibility (49), and partial separation of a separate FSH-releasing activity has been achieved (50), no specific FSH-releasing factor has been isolated or found to be released into hypophyseal portal blood. Whether the non-GnRH-associated excursions in FSH secretion represent responses to a yet to be identified hypothalamic FSH-releasing factor remains to be determined.
Basal component of FSH secretion
In addition to the episodic component of FSH release discussed,
several lines of evidence have suggested that a large portion of
circulating FSH results from basal secretion. First, circulating FSH
concentrations remain detectable for several days in sheep after
interruption of hypothalamic inputs to the pituitary (51) and in
hypophysectomized rats bearing pituitary transplants under the kidney
capsule (52). Second, FSH continues to be secreted in long term
pituitary cultures (53) while LH secretion declines. The in
vivo studies discussed earlier (7, 8, 9, 10, 51, 52), have used
peripheral FSH measurements and do not provide direct evidence for a
basal mode of FSH secretion. The results of this study provide direct
evidence that not only does a basal mode of FSH secretion exist, but
this is the dominant mode of FSH secretion in ovariectomized ewes.
Considering that the dominant component of FSH secretion is not episodic in the employed ovariectomized model with its high frequency, high amplitude patterns of GnRH (11, 54), the relevance of the pulsatile component of FSH release during the estrous cycle needs to be addressed. Here, GnRH pulses are of much lower amplitude (54). GnRH neutralization studies have revealed that blockade of GnRH input, while having little effect on peripheral FSH secretion (55), may be relevant in inducing paracrine factors, such as follistatin (56, 57), that may be involved in the control of basal FSH secretion.
Hypophyseal portal blood as a means to assess active secretion of
FSH
Demonstration of the two modes of FSH secretion was made possible
because the secretory signal can be monitored with high resolution in
hypophyseal portal blood free from the influence of dispersion and
clearance in the circulation. Because rates of changes in hormone
concentrations in hypophyseal portal samples are far more rapid than
those in the periphery, we believe that FSH patterns in the hypophyseal
portal samples approximate the actual secretory dynamics of FSH more
closely than those obtained by other reported approaches.
An important caveat that needs to be addressed relates to the means by which FSH enters the hypophyseal portal circulation. Does FSH in hypophyseal portal blood represent leaching from damaged cells or active secretion? The discreteness of the LH and FSH episodes, the one to one relationship of GnRH with LH and FSH, their immediate blockade after GnRH antagonist administration (35), and the constancy of secretion (perifusion studies suggest that damaged cells deplete their content and do not respond to secretagogues) all suggest that the FSH we measure in pituitary portal blood reflects primarily secretion and not leakage from damaged pituitary cells. As for the site of origin of the FSH in hypophyseal portal blood, there are three possibilities: 1) active secretion of gonadotropes located in pars tuberalis, 2) retrograde blood flow from pituitary to the hypothalamus, and 3) drainage from pituitary sinusoids.
Secretion vs. clearance
Considering that hypophyseal portal measurements provide more
accurate assessment of what is being secreted, an important question
arises. How meaningful are jugular FSH measurements in assessing FSH
secretory dynamics? This question is particularly relevant because
peripheral blood is the only convenient means available for monitoring
FSH. Because peripheral measurements are influenced by the rates of
secretion, clearance, and degradation, caution needs to be exercised
when drawing conclusions concerning the secretory nature of FSH from
peripheral measurements. Clearly, some conclusions, such as the dual
mode of FSH release, hold true regardless of whether the measurements
are made at the hypophyseal portal or peripheral level. Nonetheless,
peripheral measurements have failed to provide a true nature of
secretory events such as the discreteness of the GnRH-associated pulses
of FSH and the close time lag relationships of GnRH and FSH.
As a result of dispersion, the fold difference in hypo-physeal portal and peripheral FSH concentrations was much higher when the comparison was made at the pulsatile component of release (~18-fold) than at the basal component of release (~8-fold). Additionally, the half-time disappearance rate of FSH pulses at the periphery, about 25 min, is shorter than the reported half-life of FSH (3–6 h) (22, 23, 24). These results suggest that FSH secreted in pulses may be cleared faster from the circulation than that secreted in the tonic mode. Because assessments of half-life in the past have been computed on the basis of exogenous FSH, the long half-life estimates computed this way may reflect the nature of administered FSH and may not apply to what is secreted within a FSH pulse. Supportive evidence for such a concept comes from our studies in patients with Kallman’s syndrome in whom administration of GnRH led to the release of short-lived isoforms of FSH (26).
The difference in half-life, however, does not explain why the relative magnitude of changes in LH and FSH differed within a given sample between the hypophyseal portal and peripheral circulations. These differences, although intriguing, lend support to the view that gonadotropes are distributed differentially among different portions of the pituitary (58, 59). Gonadotropes are comprised of a heterogeneous population of cells, some producing LH, some producing FSH, and others producing both (60). Therefore, from a quantitative perspective, the proportions of LH and FSH measured in the hypophyseal portal blood circulation appear more a representation of their production in the lesioned part of the pituitary and not a quantitative estimate of pituitary secretion as a whole. Because the sampled hypophyseal portal plasma may represent an unknown fraction of the total secretory output, the patterns of FSH in the hypophyseal portal plasma should be used merely as guides, providing an insight into the dynamics of pituitary FSH secretion, and not to calculate total secretion.
In summary, characterization of FSH secretory profiles in the hypophyseal portal blood from ovariectomized ewes reveals a dual mode of FSH secretion, basal and episodic. Furthermore, a close one to one relationship exists between GnRH and FSH pulses, suggesting that GnRH is a regulator of episodic FSH secretion. Finally, identification of non-GnRH-associated excursions of FSH secretion supports the possibility that other, yet to be identified, factors may be involved.
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Acknowledgments |
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Footnotes |
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2 Present address: Center for Biostatistics and Epidemiology,
Pennsylvania State University College of Medicine, 500 University
Drive, Hershey, Pennsylvania 17033.
Received July 31, 1996.
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in hypophyseal portal and peripheral
blood, respectively).
