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Reproductive Sciences Program and the Departments of Obstetrics and Gynecology, Biology, and Physiology, University of Michigan, Ann Arbor, Michigan 48109
Address all correspondence and requests for reprints to: Dr. Douglas L. Foster, Reproductive Sciences Program, Room 1101SW, 300 North Ingalls Building, University of Michigan, Ann Arbor, Michigan 48109-0404. E-mail: dlfoster{at}umich.edu
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Abstract |
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The second study tested the hypothesis that diet-induced
hypogonadotropism is the result of actively inhibited central
mechanisms by investigating the effects of the nonspecific central
nervous system inhibitor, sodium pentobarbital, on pulsatile LH
secretion in the growth-restricted lamb. Serial blood samples were
collected from 11 ovariectomized lambs that were maintained at weaning
weight (
20 kg) by reduced diet. After a 4-h pretreatment period, six
of the lambs were anesthetized with sodium pentobarbital for 4 h;
the other five lambs were untreated and served as controls.
Pentobarbital anesthesia reduced the LH interpulse interval (increased
the frequency) and increased mean LH levels.
These findings suggest that during growth restriction hypogonadotropism arises from a central inhibition of GnRH neurons and is manifest as a decrease in both frequency and amplitude of GnRH pulses.
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Introduction |
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To investigate how nutritional and growth-related cues time the increase in LH secretion during sexual maturation, we used as an experimental model ovariectomized lambs that are maintained on restricted diet after weaning to retard growth (13, 15). Such lambs remain hypogonadotropic even in the absence of inhibitory ovarian steroid feedback. They respond normally to physiological doses of GnRH, indicating that the pituitary can function adequately (15). Hypothalamic GnRH content is similar in these lambs with a low LH pulse frequency (less than one pulse per 4 h) and in lambs fed ad libitum with a high LH pulse frequency (four or five pulses per 4 h) (16). Further, an increase in the number of GnRH-containing neurons has been observed in the medial basal hypothalamus of growth-restricted lambs compared with that in normally growing lambs (17). Taken together, these data from our animal model suggest that it is unlikely that a decrease in GnRH synthesis underlies hypogonadotropism during chronic low nutrition. Rather, GnRH secretion appears to be limited. This consideration is supported by the ability of an excitatory amino acid analog, N-methyl-D,L-aspartate, to induce repeated release of LH in the growth-restricted hypogonadotropic lamb (16).
The reduced LH pulse frequency observed in such lambs could reflect reduced GnRH pulse frequency. Alternatively, GnRH pulse frequency could be normal, but pulse amplitude could be reduced, and periodically a pulse attains an amplitude sufficient for LH release. Finally, a combination of these two possibilities might be responsible for the diet-induced hypogonadotropism. Our approach to this issue was to examine simultaneously the pattern of GnRH in pituitary portal blood and LH in jugular blood in growth-restricted and normally growing female lambs.
In our second experiment, we investigated the possibility that this decreased GnRH secretion may be due to central nervous system inhibition of the GnRH neurons. Our approach was to evaluate the effects of nonspecific neural inhibition by sodium pentobarbital on pulsatile LH secretion during diet-induced hypogonadotropism.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and 2).
The usual diet (20-kg lambs, 300 g/day or 500 Cal; 28-kg lambs,
450 g/day or 750 Cal) was approximately 25% of the nutrient
requirement for a normally growing 20-kg lamb and approximately 37%
for a normally growing 28-kg lamb (18). The young females were weighed
weekly, and feed intake was adjusted to maintain the 20- or 28-kg
target weight. As evidenced from observations made several times daily,
the lambs were active and healthy despite the reduced caloric intake.
The normally growing group was fed alfalfa hay and the same commercial
pelleted ration, and they exhibited rapid growth, as evidenced from
measurements of body weights at weekly intervals.
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Experimental design
Exp 1: portal surgery and blood collection. At approximately
50 weeks of age, a device designed for the collection of hypophyseal
portal blood was installed into each lamb by a modification of the
technique used by Caraty et al. (19) as previously described
(20). After surgery, the lambs were again group housed and returned to
their dietary treatments.
On the day of sample collection, 1 week after installation of the device, the lambs were maintained unrestrained in separate stalls, where they were free to behave normally. To prevent isolation stress, samples were collected from at least two lambs at a time. The animal room was adjacent to the room containing the peristaltic pumps (Minipuls 3, Gilson, Middleton, WI) and ice bath-fraction collector for collecting portal and jugular blood samples. Two hours before the start of the sampling period, each growth-restricted lamb initially received 7,000 U heparin (iv) every 30 min, and each normally growing lamb initially received 20,000 U heparin (iv) every 30 min. Throughout the blood collection period, a maintenance dose of 16,000 U/h was infused into a jugular vein via a peristaltic pump. Sequential samples of pituitary portal blood and jugular blood were collected simultaneously every 5 min for 4 h as described previously (20). Portal blood (1.5–3 ml) for the determination of GnRH was continuously aspirated through the lower guide tube into chilled test tubes containing 0.5 ml bacitracin (3 x 10-3 M; Sigma, St. Louis, MO) to reduce the degradation of GnRH. Jugular blood (2 ml) for the determination of LH was similarly collected through a catheter into chilled test tubes. Within 1 h of collection, blood samples were centrifuged, and plasma was separated and rapidly frozen. Portal and jugular blood hematocrits were monitored every hour to check for possible contamination of the portal blood samples with cerebrospinal fluid (negligible in the present study) and to assess the health status of each lamb. After the collection period, each lamb was euthanized using a barbiturate overdose (Beuthanasia-D Special, Schering Plough Animal Health Corp., Kenilworth, NJ). The placement of the portal blood collection device and the position of the lesion on the face of the pituitary were verified.
Exp 2: anesthesia and blood collection. Serial blood samples were collected from all 11 lambs every 12 min for 8 h via a jugular catheter or by jugular venipuncture (if the cannula became blocked) during the period of anesthesia. The first 4 h served as a pretreatment control period to confirm that the lambs were hypogonadotropic. Six of the lambs were then anesthetized for the remaining 4 h, and the other 5 lambs served as untreated controls. Anesthesia was induced with a single dose of 325–390 mg sodium pentobarbital (Butler Co., Columbus, OH) beginning at 1200 h. Supplemental doses (30–100 mg) were administered during the 4-h treatment period to maintain a relatively light level of barbiturate anesthesia (plane 1 of stage 3), as monitored by testing digital and eye reflexes (21).
LH and GnRH RIAs
LH was measured in duplicate 25- to 200-µl aliquots of plasma
(Exp 1) or serum (Exp 2) using a modified RIA (16, 22) developed by
Niswender et al. (23). Assay sensitivity, defined as 2
SD from maximum binding, averaged 0.7 ng/ml (Exp
1, n = 3 assays) or 0.5 ng/ml (Exp 2, n = 8 assays) for 200
µl serum, expressed relative to NIH LH-S12. Intra- and interassay
coefficients of variation for 50-µl samples of a serum pool
containing 7.2 ng/ml LH, which inhibited binding of labeled ligand to
56%, averaged 10.3% and 6.1% (Exp 1) or 11.3% and 12.1% (Exp 2),
respectively.
GnRH was measured using a previously described RIA (24, 25) that was
modified with use of the antiserum BDS 4/85, diluted at 1:400,000 (20).
Briefly, portal blood samples (750 µl, containing 600 µl plasma
and 150 µl bacitracin) were extracted with methanol and evaporated
to dryness, then reconstituted in assay buffer [PBS (pH 7.4),
containing 0.1% gelatin and 0.1% NaN3]. The
corrected plasma volume was 240 µl/assay tube based on the collection
of a 2-ml portal blood sample with 0.5 ml bacitracin. Procedural blanks
within assays consisted of extracts of peripheral samples taken into
bacitracin (750 µl), bacitracin alone (750 µl), assay buffer (750
µl), and methanol (2 ml). Extracts were assayed in duplicate 50-µl
aliquots, with all samples for each lamb measured in a single assay.
Intraassay variation, based on the median variance ratio of assay
replicates, averaged 0.05 ± 0.01. Assay sensitivity averaged
0.16 ± 0.06 pg/tube; n = 8 assays); displacement of
[125I]GnRH to 50% of the buffer controls was
8.26 ± 0.17 pg/tube. To determine cross-reactivity with
peripheral plasma substances, 750-µl aliquots of four jugular plasma
samples collected from each lamb at the beginning, middle, and end of
the sampling series were processed as portal samples (i.e.
extracted in methanol and reconstituted) and assayed simultaneously
with the portal samples. There was minor activity detected in
peripheral plasma of most (93%) lambs. To calculate the final value
for GnRH, an average value for the interfering plasma activity was
determined from the four estimates for each animal, and this plasma
blank was subtracted from the measured value for GnRH. The recovery
rate was determined by adding a known quantity of GnRH (5 pg) to
jugular plasma samples and then by assaying them at the same dilutions
as plasma samples without GnRH. The recovery rates were usually 100%;
if less, plasma concentrations were corrected for losses. As justified
previously, GnRH concentrations are expressed as the rate of collection
(picograms per min), rather than the concentration (picograms per ml),
primarily to account for changes in sample collection rate that are
independent of a change in GnRH secretion rate (24).
Data analyses
GnRH and LH pulses were identified by the Cluster pulse
detection method of Veldhuis and Johnson (26). Respective sizes of
nadir and peak cluster were 2/1 points for GnRH and 2/2 points for LH.
The t statistics for significant increases and decreases
were 3.8/3.8 for GnRH and 2.6/2.6 for LH. GnRH values were calculated
in terms of collection rate, and therefore, the size of the GnRH pulse
was considered as the total amount of GnRH in samples included within a
detected pulse. Interpulse interval was the duration between two pulse
peaks. If one pulse was observed, then the interpulse interval was the
duration from the beginning of the sampling or treatment period to the
pulse peak. If no pulse was evident, then the interpulse interval was
considered as the sampling or treatment period length (4 h in both
experiments).
Due to the large degree of variance that occurs between GnRH and LH secretion of normally growing and growth-restricted lambs, all data for Exp 1 were transformed before statistical analysis. Amplitude and mean values were multiplied by 10, then normalized by log transformation, whereas interpulse interval values were normalized by square root transformation. Further post-hoc tests were conducted using one- or two-tailed t tests with Bonferroni adjustment. Significant differences between the two treatment groups within each age were determined via one- or two-tailed t tests (StatView 512+, Brainpower, Las Calabas, CA).
In Exp 2, the LH interpulse interval and mean LH level were compared between the control and treatment groups by a single factor between-subject ANOVA (StatView 512+, Brainpower). Mean LH pulse amplitudes before and during anesthesia were compared, in lambs in which pulses were observed, by a single-factor within-subject ANOVA. The Scheffe test was used in any post-hoc comparisons made among means.
Differences between means were considered significant at the P < 0.05 level. Undetectable GnRH and LH levels were assigned a value equivalent to the limit of detection of the assay.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As shown in Figs. 3 and 4, the growth-restricted females were
hypogonadotropic and exhibited a long LH interpulse interval (mean
± SE, 3.43 ± 0.38 h) compared with the normally
growing females (0.70 ± 0.18 h). The GnRH pulsatile
secretion rate was also reduced in the growth-restricted lambs compared
with that in the normally growing females (Figs. 3 and 4).
Growth-restricted females exhibited a longer GnRH interpulse interval
(2.08 ± 0.52 h) compared with normally growing females
(0.90 ± 0.45 h).
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).
However, the range of total GnRH release per pulse was greater in the
growth-restricted females (1.01–101.94 pg/pulse) than that in the
normally growing females (1.79–31.47 pg/pulse).
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In contrast, only 17.6% of GnRH pulses (3 of 17) induced a LH pulse in the growth-restricted females, and only 1 of the 14 noncoincident GnRH pulses induced a rise in LH at the end of a sampling period that did not fit the criteria for a LH pulse. The amplitude of the remaining 13 GnRH pulses (5.45 ± 1.06 pg/pulse) that did not produce a LH pulse in the growth-restricted females was 1/10th of that which did induce a LH pulse (50.60 ± 26.05 pg/pulse).
Exp 2
During the 4-h pretreatment control period, all lambs (n =
11) exhibited either zero or one LH pulse (mean ± SE,
0.6 ± 0.2 pulse/4 h; Fig. 6), a
frequency typical of growth-restricted lambs (15). The LH pulse pattern
changed during anesthesia, as evidenced by the significant decrease in
interpulse interval (preanesthesia, 3.47 ± 0.23 h; during
anesthesia, 1.33 ± 0.42 h; Fig. 7). No change in interpulse interval
occurred in the untreated lambs (3.32 ± 0.66 vs.
3.24 ± 0.76 h; Fig. 7). In the five lambs that exhibited
pulses during anesthesia, all occurred during the first 2 h of
treatment, thereby disrupting the low frequency, regularly spaced, LH
pulse pattern of the growth-restricted lamb. This latter pattern has
been documented previously in growth-restricted lambs in which frequent
blood samples were collected for 28 h (15). In that study, all but
one female (n = 7) exhibited an interpulse interval greater than
7.5 h.
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, black triangles). The
mean LH pulse amplitude during anesthesia was not different from that
before anesthesia in lambs in which LH pulses occurred during both 4-h
periods (5.7 ± 1.0 vs. 6.4 ± 0.8 ng/ml; n =
4). Finally, mean LH levels were greater during the 4 h of
anesthesia (n = 6 lambs) compared with levels in the untreated
group during the same 4-h period (n = 5 lambs; 1.7 ± 0.3
vs. 0.8 ± 0.2 ng/ml, respectively).
Of the anesthetized lambs, one did not exhibit any LH pulses during
anesthesia (lamb 966; Fig. 6), although a small fluctuation above
baseline occurred when the other five lambs all produced extra LH
pulses. It is noteworthy that in this lamb, the interval between the
inductive dose of anesthesia and the first maintenance dose of
pentobarbital was more than twice as long as that for the other five
lambs (51 vs. 23.2 ± 1.5 min, respectively). This
suggests that the initial depth of anesthesia was much greater in the
former lamb.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our study investigating the pattern of GnRH in the pituitary portal circulation provides direct evidence that both frequency and amplitude of GnRH secretion are altered by nutrition. Significantly fewer GnRH pulses were measured in the growth-restricted females compared with the normally growing females, suggesting that diet-induced growth restriction causes a decrease in GnRH pulse frequency. However, not all of the GnRH pulses stimulated LH release, such that LH pulse frequency was much lower than GnRH pulse frequency. Low amplitude GnRH pulses (pulse size, as measured by picograms per pulse) that did not induce coincident LH pulses were found in four of seven growth-restricted lambs.
There are several possible explanations for the observation of these small GnRH pulses with no coincident LH pulses. In the process of collecting blood from the portal circulation, some of the portal blood vessels are cut, which would ordinarily transport GnRH to the anterior pituitary. Thus, in four of the growth-restricted lambs, blood supply to the pituitary may have been compromised to such an extent that smaller sized GnRH pulses were not large enough to induce a LH pulse. This possibility seems unlikely for several reasons. First, the LH interpulse interval measured in the growth-restricted lambs is similar to that observed in other studies (including Exp 2) in which portal blood collection does not take place. This implies that the extra GnRH pulses observed in portal blood do not normally induce LH pulses in the growth-restricted lamb. Second, if portal blood collection compromised the signal from smaller GnRH pulses, then a similar phenomenon of a lack of coincidence between smaller GnRH pulses and LH pulses would also be expected in the normally growing lambs. This is not the case. Small GnRH pulses are present in most of the normally growing lambs, and in the majority of cases, they induce a coincident LH pulse.
A second possibility could be that there is a decrease in the pituitary response to GnRH in the growth-restricted females, such that small amplitude GnRH pulses no longer induce the LH response that would normally occur in the absence of food restriction. LH pulses in response to physiological doses of exogenous GnRH have previously been reported in growth-restricted female lambs (16), but a direct comparison of the response to similar doses in rapidly growing lambs was not investigated in that study. Studies in other developing animals suggest that the sensitivity of the pituitary during times of metabolic challenges is compromised in some species, but not in others. In the young growth-restricted rat, pituitary responsiveness to GnRH is not altered by food restriction (28, 29), but it is reduced in the female cow and pig (7, 30). The possibility remains, therefore, that although the pituitary of the growth-restricted lamb can respond to GnRH pulses, these pulses must be of a sufficient magnitude to induce a LH pulse.
A third possibility is that rapid, but low amplitude, GnRH pulses occur normally, and these are interspersed periodically with high amplitude GnRH pulses that produce a coincident LH pulse. The low amplitude GnRH pulses are more visible in the growth-restricted lambs, because the overall frequency of GnRH episodes is much less compared with that in the normally growing animals. If hypothalamic multiunit activity reflects GnRH neurosecretory activity, as has been suggested in studies using the goat (31), then measuring multiunit activity within the hypothalamus might help to resolve this problem.
A physiological function has been postulated for small amplitude GnRH pulses that do not induce a coincident LH pulse (32). It has been suggested that such pulses might maintain LH and FSH synthesis without releasing the gonadotropins and that such pulses might also modify pituitary responsiveness to large GnRH pulses. Although the LH pulses that were detected in the growth-restricted lambs were larger in amplitude compared with those in the normally growing lambs, such a possibility has not been investigated directly in the young lamb with or without food restriction.
Although our results suggest that the decrease in LH secretion caused by food restriction is due to a decrease in both GnRH pulse frequency and amplitude, a study using push-pull cannula sampling in growth-restricted lambs showed a decrease only in GnRH pulse amplitude (33). This former study was unable to detect a decrease in LH pulse frequency during the growth restriction period compared with that in ad libitum-fed lambs even though the animals used were ovary intact and still experienced steroid negative feedback. This lack of a suppression of LH pulse frequency due to food restriction is surprising, as it is well documented in many species in both the presence and absence of ovarian steroids [sheep (13, 34), rat (10), pig (35), and monkey (36)]. Perhaps the food restriction was insufficient to produce a decrease in GnRH and LH pulse frequency. With a more intense restriction, a decrease in frequency would be expected to occur.
In a previous study we observed that the distribution of GnRH neurons is different in the nutritionally growth-restricted lamb from that in the normally growing lamb (27). We found a dramatic increase in GnRH-containing neurons in the medial basal hypothalamus, which could be responsible at least in part for the decrease in release of GnRH in growth-restricted lambs, perhaps by activation of an inhibitory GnRH neuronal population exerting an ultrashort loop feedback on its own release (37, 38, 39, 40, 41). Another possibility is that GnRH is not released from this population of neurons due to increased activity of inhibitory neurotransmitter pathways or to decreased activity of stimulatory pathways.
We addressed this last possibility in our second study and found that in the hypogonadotropic growth-restricted lamb, pentobarbital anesthesia transiently increases pulsatile LH secretion. As pentobarbital does not affect the pituitary response to GnRH (42, 43, 44), it is likely that the anesthetic acts in the brain to alter GnRH secretion. Studies in vitro have demonstrated that administration of pentobarbital to cultured mammalian central nervous system neurons abolished all spontaneous synaptic activity (45). Thus, the appearance of one or two extra LH pulses during the first 2 h of anesthesia in the present investigation suggests that pentobarbital initially suppressed the activity of putative inhibitory neurons that impinge directly or indirectly on the GnRH neurosecretory cells. This leads to the conclusion that the decreased GnRH secretion in the hypogonadotropic growth-restricted lamb may be due at least in part to central inhibition of the GnRH neurons.
One of the most likely candidates that could provide a link between metabolic signals and the reproductive system is the peptide neurotransmitter, neuropeptide Y (NPY). NPY plays a central role in energy homeostasis, causing hyperphagia and foraging behavior during periods of reduced food intake (46, 47, 48, 49, 50, 51, 52). In addition, NPY infusion into the lateral ventricle inhibits the onset of estrous cycles during realimentation in female rats with delayed puberty due to growth restriction (53). The population of NPY neurons that might link metabolism and reproduction is probably located within the arcuate nucleus of the hypothalamus (ARC) and projects to the paraventricular nucleus and the dorsomedial nucleus (see Ref. 54 for review). During fasting, messenger RNA levels increase in the ARC, and NPY levels increase in the ARC, paraventricular nucleus, and dorsomedial nucleus. Thus, the decrease in GnRH and LH secretion associated with food deprivation may be due to NPY neurons projecting to the median eminence from the ARC and decreasing GnRH secretion, or they may take a more indirect route.
In summary, the data reported herein provide initial support for the hypothesis that inhibitory neurons are activated in response to metabolic cues that depress both the frequency and amplitude of GnRH release. The site of action and the nature of these inhibitory neurons remain to be determined.
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Acknowledgments |
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Footnotes |
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Received July 8, 1999.
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