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Wisconsin Regional Primate Research Center and Department of Pediatrics University of Wisconsin, Madison 53715-1299
Address all correspondence and requests for reprints to: Ei Terasawa, Ph.D., Wisconsin Regional Primate Research Center, 1223 Capitol Court, Madison, Wisconsin 53715-1299. E-mail: terasawa{at}primate.wisc.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-Amino butyric acid (GABA) is the major inhibitory neurotransmitter
in the hypothalamus (9). The inhibitory role of GABA in the
preovulatory gonadotropin surge and puberty has been reported in rats
and sheep (10, 11, 12). Previously, we have hypothesized that the LHRH
neuronal system in primates is tonically inhibited by GABA neurons
before the onset of puberty and that reduction of GABA inhibition
triggers the onset of puberty. This hypothesis is based on several
observations in this laboratory. First, GABA levels in the stalk-median
eminence (S-ME) in prepubertal monkeys were much higher than in
midpubertal monkeys (13, 14). Second, the GABAA receptor
blocker, bicuculline, but not the GABAB receptor blocker,
saclofen, stimulated LHRH release in prepubertal monkeys by removing
endogenous GABA inhibition (13), whereas exogenous GABA was not
effective in suppressing LHRH release until after the onset of puberty
(13), when endogenous GABAergic tone is reduced. Third, infusion of
antisense oligodeoxynucleotides for glutamic acid decarboxylase (GAD67
and GAD65) messenger RNAs (mRNAs) into the S-ME of prepubertal monkeys
resulted in a dramatic increase in LHRH release (15, 16), presumably
due to the reduction of synthesis and release of GABA. GAD67 and GAD65,
derived from two different genes, are the catalytic enzymes for GABA
synthesis from glutamate. In vivo perfusion of an antisense
oligodeoxynucleotide for GAD67 mRNA into the S-ME of pubertal monkeys
also resulted in an increase in LHRH release, but the magnitude of this
increase was much smaller than that seen in prepubertal monkeys (16),
indicating that GABA inhibition is not completely removed at the onset
of puberty, but is weakened. Fourth, the antisense GAD 67-induced LHRH
increase was accompanied by a decrease in GABA release, followed by an
increase in glutamate release (14).
If GABA is an inhibitory neurotransmitter responsible for the timing of puberty, infusion of the GABAA receptor blocker, bicuculline, into the base of the third ventricle above the ME would trigger puberty by reducing endogenous GABA input to the LHRH neuronal system. In the present study, we examined this possibility. The results indicate that bicuculline infusion induces precocious puberty in female rhesus monkeys.
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Materials and Methods |
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Surgery
To infuse bicuculline into the base of the third ventricle, all
monkeys received stereotaxic implantation of a stainless steel cannula
with a double lumen (20-gauge outer cannula and 23-gauge inner cannula)
into the base of the third ventricle (Fig. 1
) under isoflurane anesthesia. The third
ventricle and bone structures were visualized with x-ray
ventriculograms before cannula implantation, as described previously
(17). The cannula was secured with dental acrylic and screws to the
skull, and the inner cannula was connected to either a SILASTIC brand
silicon tube (Dow Corning, Midland, MI) or tygon
tube, which was exteriorized between the shoulder blades. The tube was
then connected to a small portable infusion pump (Disetronic Medical Systems, Inc., Minneapolis, MN).
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Observation of developmental processes
Hormonal and physical changes during pubertal development were
obtained as follows. Weekly blood samples were taken via femoral
puncture at 0830 and 2030 h on the same day, starting at least 3
weeks before surgery until the confirmation of two ovulations in all
animals. Body weight was also measured weekly. To keep animals as
undisturbed as possible, more frequent blood sampling was not
conducted. Sex-skin color index, menarche, and subsequent menstruations
were observed and recorded daily as described previously (6). The
occurrence of ovulation was assessed by the break-down of sex-skin
color followed by progesterone levels above 1 ng/ml (6).
Hormone assays
LH, FSH, estradiol, progesterone, and GH in serum samples were
measured by RIA. LH and FSH levels were measured in all samples.
However, due to the limited volume, estradiol was measured in morning
samples, whereas progesterone and GH were measured in evening samples.
To confirm ovulation, progesterone levels in the morning samples were
also measured when evening levels reached >1 ng/ml. Assays for LH,
estradiol, and progesterone, were described previously (5, 6, 18). FSH
levels were estimated by a heterologous immunoassay with antiovine FSH
(H-31, supplied by Dr. Gary D. Hodgen), human FSH trace (hFSH-I-3,
National Hormone Pituitary Program, 4822B), and reference preparation
(cynFSH-RP-1, National Hormone Pituitary Program). The sensitivity was
3 ng/ml, and the intra and interassay coefficients of variation (cv)
were 3.8% and 12.6%, respectively. The results from the FSH assay
have been reported (19). For GH assay we employed antihuman GH
(National Hormone Pituitary Program, C11981B) for the 1st antibody,
monkey GH (National Hormone Pituitary Program, 5892C) for trace, and
human GH-RP1 (National Hormone Pituitary Program, 4793B) for the
standard. Sensitivity was 0.1 ng/ml and the intra and interassay cv
were 3.9% and 6.1%, respectively.
Statistical analysis
The average age in months at menarche, first ovulation and
second ovulations were compared among the three groups, using ANOVA
followed by a post hoc analysis with
Student’s-Newman-Keuls’ multiple range test. The body weights at
menarche, and first and second ovulations among groups were similarly
compared. Effects of the bicuculline treatment on the LH, FSH, estrogen
and GH levels, and developmental changes in LH, FSH, estrogen, and GH
were examined with two-way ANOVA, followed by a post hoc
analysis using the Student-Newman-Keuls’ multiple range test.
Significance was set at P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and Fig. 2A).
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, Fig. 2B) than that of
saline controls (44.8 ± 1.8) and colony controls (44.7 ±
1.2). Similarly, the age (33.7 ± 2.9 months) of second ovulation
in bicuculline-treated animals was younger (P < 0.001,
Table 1, Fig. 2C) than that of saline controls (46.1 ± 2.0) or
colony controls (45.7 ± 1.2).
The interval between the menarche and first ovulation in bicuculline-
and saline-treated group was not significantly different (13.3 ±
2.9 vs. 16.7 ± 2.9 months). The interval between first
and second ovulations (2.6 ± 0.7 months, Table 1, Fig. 3) in the bicuculline-treated animals
tended to be longer than that in colony controls (1.2 ± 0.1
months) as well as saline controls (1.3 ± 0.3 months, Table 1,
Fig. 4), although the means were not
significant (P < 0.1 for both).
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2. Hormonal changes
In the bicuculline-treated animals, the nocturnal increase in LH
release started to occur shortly after the initiation of bicuculline
infusion as shown in Fig. 3A. In contrast, in saline controls, the
nocturnal LH increase did not occur until around or after 20 months of
age (Fig. 4A). Group data (Fig. 5)
indicated that there were developmental changes in LH release in both
bicuculline and saline groups (P < 0.001 for both).
The treatment effect of bicuculline was significant for both the
morning and evening values (P < 0.05 and
P < 0.001, respectively). Further, evening LH values
were significantly higher than morning LH values in both bicuculline
and saline groups (P < 0.005 for mornings and
P < 0.001 for evening). However, the significant
interaction between the treatment effect and age or the morning-evening
effect and age was not observed.
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), whereas the
pubertal increase in FSH did not occur until 2–3 months before
menarche in saline controls (Fig. 4B). There were clear developmental
effects on FSH in both bicuculline and saline groups (P
< 0.01 for both, Fig. 6) and there was a
significant effect of bicuculline on FSH levels (P <
0.01, Fig. 6). Post hoc analysis indicated that FSH levels
in the bicuculline-treated group were significantly higher than those
in the saline group between 16–27 months of age (Fig. 6).
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), whereas it did not start to increase
until a few months before menarche in the saline group (Fig. 4C).
Analysis of group data indicated that there were clear developmental
changes in estrogen in both groups (P < 0.01 for
both), and there was a bicuculline treatment effect on estrogen levels
(P < 0.05, Fig. 7).
Post hoc analysis showed that estrogen levels in the
bicuculline group were significantly higher than those in the saline
controls at 16–19 months and 24–29 months of age (Fig. 7). Repeated
elevations of progesterone above 1 ng/ml in bicuculline-treated monkeys
(Fig. 3C) before 30 months of age indicated that they ovulated at a
younger age than saline controls (Fig. 4C). Progesterone levels
(1.8 ± 0.5 ng/ml) at first ovulation in the bicuculline-treated
monkeys tended to be lower than those (2.7 ± 1.4 ng/ml) in saline
controls (not significant), but were significantly lower than in colony
controls (3.9 ± 0.6 ng/ml, P < 0.02).
Progesterone levels (1.9 ± 0.3 ng/ml) at second ovulation in the
bicuculline-treated monkeys were significantly lower than those in
saline controls (5.9 ± 1.0 ng/ml, P < 0.01) as
well as in colony controls (3.5 ± 0.5 ng/ml, P <
0.01).
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).
However, while GH levels in saline controls became low by 20 months of
age, and remained low through two ovulations (Fig. 8B), high GH levels
in bicuculline animals continued through two ovulations (Fig. 8A).
Group data indicated that there was a significant effect of the
bicuculline treatment on GH (P < 0.01, Fig. 8C).
Post hoc analysis indicated that mean GH levels in the
bicuculline group at 20–31 months of age were higher than those in the
saline group (Fig. 8C).
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). The body weights
of bicuculline-treated monkeys were consistently higher than that of
colony controls or saline controls, until 32–34 months of age (Fig. 9, P < 0.001). In
contrast, the body weights of saline controls were consistently smaller
than colony controls until age of first ovulation (Fig. 9, P < 0.001). Nonetheless, the body weights at menarche,
first ovulation, and second ovulation in bicuculline-treated monkeys
were only lower than those of colony controls, but did not differ from
those of saline controls (Table 1).
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Discussion |
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The observation that increases in circulating LH, FSH, and estrogen occurred 2–3 weeks after the initiation of bicuculline infusion suggests that the blockade of GABAA receptors indeed stimulated LHRH release from the hypothalamus. Previously, we have shown that direct infusion of bicuculline into the S-ME stimulated LHRH release (13). Thus, the reduction in GABA triggers the cascade of LHRH release, followed by gonadotropin and estrogen secretion, and subsequent menarche occurring at 6–20 weeks. In contrast to this prompt effect on age of menarche, it took an additional 8–12 months for first ovulation. Because the time between menarche and first ovulation in saline controls and colony females is 12–16 months, bicuculline infusion slightly shortened this interval. Nonetheless, the question arises as to why the bicuculline-induced LHRH increase is not sufficient to result in first ovulation right after menarche? To answer this question, we need to discuss two important points.
First, the hypothalamic mechanism involved in the timing of first ovulation appears to differ from that of menarche, even though both require an increase in pulsatile LHRH release. There are several examples of experimental manipulations in the female rhesus monkey in which the timing of first ovulation was altered without changing the timing of menarche. Transplantation of the adrenal medulla, which contains catecholamines and neuropeptide-Y (NPY), only advanced the age of the first ovulation, but not menarche (20). The long-term administration of GH into juvenile female monkeys accelerated the timing of first ovulation, but not menarche (21). Similarly, treatments with IGF-1 advanced the timing of first ovulation, whereas it did not alter the timing of menarche (22). In contrast, administration of a somatostatin analog delayed the timing of first ovulation, but not menarche (23). Further, because in the IGF-1 treatment experiment, the LH response to NMDA challenge in animals at the age of first ovulation was larger than that in animals at the menarcheal age, independent from pituitary sensitivity, Wilson (22) concluded that the sensitivity of the LHRH neurosecretory system to NMDA was altered before first ovulation.
Second, a larger amount of LHRH output appears to be required for the positive-feedback effects of estrogen in the pubertal rhesus monkey. Evidence to support this speculation is as follows: 1) Escape from estrogen suppression or a decrease in hypersensitivity to estrogen in ovariectomized female monkeys, occurred at the age of first ovulation, but not at the age of menarche (24, 25); 2) Although the positive-feedback effects of estrogen on the LH surge in ovariectomized monkeys starts to occur at the menarcheal age (26, 27), the amplitude of the LH response to estrogen continuously increases until the age of first ovulation (27); and 3) Direct measurement of LHRH release from the S-ME indicates that an increase in pulsatile LHRH release (pulse frequency, pulse amplitude, and basal release) occurs at the onset of puberty, but a total output of LHRH release (pulse amplitude and basal release) further increases between early and midpubertal stages in female rhesus monkeys (28, 29).
It has been reported that hourly infusion of LHRH (6 µg) into juvenile female monkeys by a pump, through the general circulation, resulted in menarche by 7–8 weeks followed by first ovulation by 9–10 weeks after the initiation of infusion (30). Priming the gonadotrophs by the pulsatile administration of LHRH with the same protocol in ovariectomized adult monkeys, whose LHRH pulse-generating mechanism is eliminated by lesions, is sufficient to result in the estrogen-induced gonadotropin surge (31). Therefore, the 6 µg/h infusion of LHRH is sufficient to induce menarche as well as the preovulatory gonadotropin surge in ovarian intact juvenile female monkeys. In contrast, the increase in LHRH release induced by bicuculline in this study is probably not as large as LHRH infusion by a pump (30), and thus insufficient to induce positive-feedback effects of estrogen, even though it is sufficient to result in menarche.
The results of the present study suggest that a reduction of GABA inhibition can trigger the onset of the pubertal increase in LHRH release. A series of studies from this laboratory further suggest that the reduction in GABA release is followed by an increase in glutamate release in the S-ME (14, 16). In fact, a pubertal increase in glutamate appears to occur promptly after GABA reduction. For instance, when an antisense oligodeoxynucleotide for GAD 67 mRNA was infused into the S-ME, a glutamate increase occurred shortly after a GABA reduction (14), and the antisense-GAD 67-induced LHRH release was indeed blocked by the NMDA blocker MK801 (16). Because glutamate, an excitatory neurotransmitter, plays an important role in puberty (32, 33, 34, 35), an increase in glutamate release in the S-ME undoubtedly contributes to further increase LHRH release during the progress of puberty. How quickly GABA reduction is followed by glutamate increase at the spontaneous onset of puberty has not been studied.
Systemic infusion of N-methyl-D-aspartate (NMDA) in juvenile male monkeys at 15–16 months of age resulted in testicular growth with spermatogenesis comparable to that of adult males by 16–30 weeks (36). Because the effects of NMDA were blocked by simultaneous infusion of an LHRH antagonist, it is assumed that NMDA stimulated LHRH release from the hypothalamus. Because investigation into the effects of NMDA infusion on precocious puberty in female monkeys has not been conducted, direct comparisons cannot be made. Nonetheless, the timing required for the initial response of the testis to the NMDA-induced LHRH/gonadotropin secretion (36) and that of the ovary to the bicuculline-induced LHRH/gonadotropin secretion in this study appears to be similar, although the timing required for the final maturation of the testis and the ovary with these treatments appears to be dissimilar.
There are consistent data to support the concept that the reduction in GABA is followed not only by an increase in glutamatergic input, but also by other stimulatory and inhibitory inputs to the LHRH neuronal system. We have reported that NPY and norepinephrine neuronal systems were both important for the advanced stage of puberty, rather than at the onset of puberty (37, 38). Further, evidence indicates that inhibitory opiatergic input to the LHRH neuronal system became active after the onset of puberty (39, 40, 41, 42). Therefore, it is hypothesized that the period between menarche and first ovulation is required for maturation of the stimulatory and inhibitory regulatory mechanisms for a large amount of LHRH release.
The fact that when the bicuculline infusion was terminated, precocious puberty induced by bicuculline is halted, indicates that 1) the immature hypothalamic mechanism for cyclic ovulation is driven by bicuculline infusion, and 2) GABA inhibition continues after the onset of puberty as well as after the incidence of first ovulation. A previous observation that infusion of an antisense oligodeoxynucleotide into the S-ME of pubertal monkeys stimulated LHRH release, although the LHRH response in the pubertal monkeys was much smaller than that in prepubertal monkeys (16), supports this notion.
The results that the interval between first and second ovulations in bicuculline-treated animals tended to be longer than controls, and that progesterone levels after first and second ovuations in bicuculline-treated animals were less than those in controls, appear to indicate that precoscious puberty with the GABA antagonist may not represent the normal pubertal process. Any abnormalities may be due to the parameters of bicuculline infusion, such as frequency and doses. Whether precoscious puberty by other approaches exhibits similar characteristics in the progesterone profile or this is specific to GABA disinhibition is unknown.
Saline infusion retarded body weight suggesting that the cannula placement in the third ventricle and infusion procedure were slightly stressful to the animals. However, bicuculline infusion resulted in accelerated growth, when compared with normal controls. It has been shown that the body weight increase in monkeys at 12 to 50 months is parallel to bone growth (43). Because we did not measure GH levels in untreated controls, it is difficult to speculate whether elevated levels of GH in both bicuculline-treated animals and saline controls before 19 months of age are due to maturational changes or to procedural. Nonetheless, GH levels in bicuculline-treated monkeys at 19–31 months were higher than in saline controls. These data are interpreted to mean that 1) a premature increase in estrogen with bicuculline treatment may directly stimulate epiphysial growth and indirectly stimulate it through the release of GHRH, GH and IGF-1, and/or 2) bicuculline infusion into the S-ME of juvenile monkeys disinhibits the GH-releasing hormone (GHRH) neurons/neuroterminals, thus stimulating GH release. It is of interest to further study if GABA neurons mediate the interaction between the LHRH neuronal system and/or the GHRH/somatostatin neuronal system in the hypothalamus at the onset of puberty, as well as during the progress of puberty.
In summary, in the present study pulsatile infusion of a GABAA receptor antagonist, bicuculline, advanced the timing of menarche and first ovulation. The results suggest that the reduction of inhibitory input to LHRH neurons from GABA neurons is the key factor for initiation of the onset of puberty. However, it takes several months for ovulation to occur after menarche, indicating that subsequent establishment of facilitatory and inhibitory inputs to LHRH neurons is required during the pubertal process. The mechanism of the reduction of inhibitory GABA input to LHRH release remains to be investigated.
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Acknowledgments |
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Footnotes |
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2 Present address: Department of Physiology, Yokohama City University,
School of Medicine, Yokohama, Japan.
Received May 24, 1999.
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References |
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-Aminobutyric acid is an inhibitory neurotransmitter restricting the
release of luteinizing hormone-releasing hormone before the onset of
puberty. Proc Natl Acad Sci USA 91:395–399-amino butyric acid (GABA) and glutamate in control of puberty in
female rhesus monkeys: effect of an antisense oligodeoxynucleotide for
GAD67 messenger ribonucleic acid and MK801 on luteinizing
hormone-releasing hormone release. Endocrinology 140:705–712This article has been cited by other articles:
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