Endocrinology Vol. 141, No. 4 1325-1331
Copyright © 2000 by The Endocrine Society
Alcohol Ingestion Inhibits the Increased Secretion of Puberty-Related Hormones in the Developing Female Rhesus Monkey1
W. Les Dees,
G. A. Dissen,
J. K. Hiney,
F. Lara and
S. R. Ojeda
Department of Veterinary Anatomy and Public Health, Texas A & M
University (W.L.D., J.K.H., F.L.), College Station, Texas 77843; and
Neuroscience Division, Oregon Regional Primate Research Center (G.A.D.,
S.R.O.), Beaverton, Oregon 97006
Address all correspondence and requests for reprints to: W. Les Dees, Ph.D., Department of Veterinary Anatomy and Public Health, Texas A & M University, College Station, Texas 77843-4458.
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Abstract
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Alcohol (ALC) use and abuse by adolescents has been rising at an
alarming rate. Whether ALC consumption during prepubertal years affects
specific hormones and the process of sexual maturation is not known. We
used immature female rhesus macaques to assess the effects of ALC on
circulating levels of hormones known to be critical for the pubertal
process. Ten monkeys averaging 20.3 ± 0.3 months of age were bled
by saphenous vein puncture at 0830 and 2030 h each day for 5
consecutive days to determine baseline levels of GH, insulin-like
growth factor I, FSH, LH, estradiol (E2), and leptin. For
the next 12 months, each day at 1330 h five monkeys were
administered ALC (2 g/kg), and five monkeys were administered an
isocaloric sucrose solution via a nasogastric approach. Blood was again
collected twice daily on 5 consecutive days at 24, 28, and 32 months
for hormone analysis. Food consumption and weight gain were similar for
ALC-treated and control animals. The expected night-related increase in
serum GH occurred during late juvenile development (28–32 months of
age) in control animals, but was suppressed (P <
0.05) in ALC-treated animals. This action was paralleled by a decrease
(P < 0.01) in serum insulin-like growth factor I.
Serum LH and E2 were also depressed by ALC, with their
effects most pronounced at 32 months (LH, P <
0.01; E2, P < 0.001). Serum FSH and
leptin were not altered. Although ALC did not affect age at menarche,
the interval between subsequent menstruations was lengthened
(P < 0.05), thereby showing that ALC affected the
development of a regular monthly pattern of menstruation. These results
demonstrate the detrimental effects of ALC on the activation of hormone
secretion that accompanies puberty in female rhesus monkeys. They also
suggest that the subsequent growth spurt and normal timing or
progression of puberty may be at risk in human adolescents and
teenagers consuming even relatively moderate amounts of ALC on a
regular basis.
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Introduction
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A RECENT NIH survey has demonstrated an
alarming trend of alcohol (ALC) use occurring at earlier ages, often
during adolescence (1). Interestingly, females account for the greatest
change in this drinking pattern. This nationwide study of students in
the United States indicated that ALC use begins as early as the sixth
grade, with peak initiation occurring between grades seven through
nine. The study also indicated that 24% of girls in the eighth grade
had consumed ALC within 30 days of the survey and that 14% had
consumed more than five drinks in a row on one or more occasions during
the prior 2 weeks. The increasing incidence of ALC use and abuse at
this early age is noteworthy because adolescence represents a
potentially vulnerable time for developing individuals, who may be more
sensitive to the drug and less tolerant to its detrimental effects than
adults. Whether ALC abuse alters the secretion of puberty-related
hormones at this critical time of growth and development has not been
evaluated, but this warrants serious consideration in view of the
reported affects of ALC on endocrine function of experimental animals.
The possibility that ALC could alter neuroendocrine development has
been suspected for years, as a history of any drug ingestion is
routinely investigated to identify the potential causes of altered
pubertal development or endocrine function (2). Studies using rats have
shown that ALC consumption causes delayed female puberty (3, 4) and
alters the levels of puberty-related hormones (4, 5). Even though case
studies involving ALC use and abuse by adolescent and teenage humans
are limited in number, they have suggested that the drug can disrupt
endocrine function in addition to stature and weight distribution in
young people (6, 7, 8) as well as place them at risk for nutritional
deficiencies (9). In the present study, we used female rhesus monkeys
to examine the effects of chronic exposure to a low dose of ALC on
early pubertal maturation, as assessed by developmental changes in the
secretion of specific puberty-related hormones, timing of first menses,
as well as development of a regular monthly pattern of
menstruation.
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Materials and Methods
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Animals
Ten immature female rhesus monkeys (Macaca mulata)
born and raised at the Oregon Regional Primate Research Center (ORPRC)
were used for this study. After removal from their mothers, they were
raised in a nursery with other monkeys of similar ages and had free
access to natural light from 10–11 months of age to 19–20 months of
age. The monkeys selected for the study were closely matched in age,
ranging from 19.5–22.2 months, with a mean
(±SEM) age of 20.3 ± 0.31 months. None of
the monkeys had been exposed previously to ALC or any other drug. For
the study, the monkeys were individually housed indoors with controlled
lighting (12-h light, 12-h dark cycle; lights on, 0700 h) and
temperature (22 C). They were fed monkey chow (Jumbo 537, Ralston Purina Co., St. Louis, MO) twice daily at 0800 and 1500 h.
Each monkey was fed enough food per day to equate to approximately
4–5% of body weight. The body weight of juvenile monkeys fed this
amount falls within the 50th percentile for normal weight compared with
rhesus macaques raised at the ORPRC over the last 15 yr. Food
consumption was assessed and recorded daily. The monkeys were weighted
at 2- to 4-week intervals, and the amount of food provided was adjusted
as the animals grew. This feeding regimen is routinely used by the
ORPRC for growing monkeys. Their diet was supplemented two times per
week with apple slices and three times per week with 100 g of a
mixture of corn, oats, and barley with molasses (Ralston Purina Co.) plus raisins, whole peanuts, sunflower seeds, and sweetened
breakfast cereal. Animal maintenance and research were approved by the
ORPRC institutional animal care and use committee in accordance with
the NIH policy on the use of animals in research and the Guide for the
Care and Use of Laboratory Animals. The health of the monkeys was
monitored by veterinarians in the Division of Animal Resources at the
ORPRC.
Experimental procedures
Initial blood samples were obtained from all monkeys at an
average of 20.3 months for assessment of baseline hormone levels for
GH, insulin-like growth factor I (IGF-I), FSH, LH, estradiol
(E2), and leptin. The samples (3.5 ml) were
withdrawn via saphenous vein punctures twice daily at 0830 and
2030 h for 5 consecutive days. Starting on the sixth day at
1330 h, five monkeys were administered ALC (2 g/kg; 25% ethanol
diluted in saline), and five monkeys were administered a sucrose/saline
vehicle control that was isocalorically equivalent to the
ethanol/saline solution. Both solutions were administered in equal
volumes (10 ml/kg BW) through a pediatric grade nasogastric tube
(5-French, Professional Medical Products, Inc., Greenwood, SC). To ease
insertion, the tip of the feeding tube was dipped in 2% xylocaine
jelly (Astra USA, Inc., Westbourgh, MA). The ALC and
sucrose solutions were administered every day by this procedure until
each monkey was 32 months of age. To determine the effects of ALC on
developing hormone patterns, blood samples were collected as described
above when the monkeys were 24, 28, and 32 months old. All blood
samples for hormone analysis were allowed to clot overnight, then
centrifuged, and the serum was stored at -20 C until assayed for
hormone levels.
Blood ALC analysis
Blood samples were collected via saphenous vein puncture 3
h after ALC administration, and the levels of ALC in blood were
subsequently measured in duplicate by an enzymatic method
(Sigma, St. Louis, MO) shown to be both sensitive and
reliable (10). The 3-h interval was selected because it is at this time
that ALC levels peak after intragastric administration (11, 12). The
blood ALC levels were assessed periodically by this method as well as
by monitoring blood samples taken at 0830 h to assure overnight
clearance of ALC from the blood.
Hormone analysis
Monkey FSH and LH were assessed in serum using kits obtained
from the National Hormone and Pituitary Program, NIDDK. Assay
sensitivity for FSH was 0.4 ng/ml, and the intra- and interassay
variations were 2.0% and 3.5%, respectively. The sensitivity of the
LH assay was 0.07 ng/ml, and the intra- and interassay variations were
3.4% and 5.6%, respectively. Serum GH and IGF-I were assessed using
human kits purchased from Diagnostics Systems Laboratories, Inc. (Webster, TX). The sensitivity of the GH assay was 0.1
ng/ml, and the intra- and interassay variations were 4.2% and 6.3%,
respectively. Assay sensitivity for IGF-I was 5.0 ng/ml, and the intra-
and interassay variations were 3.0% and 6.1%, respectively. Serum
E2 was assessed using a human kit purchased from
Diagnostic Products (Los Angeles, CA) with an assay
sensitivity of 5.0 pg/ml, and the intra- and interassay variations were
4.3% and 6.4%, respectively. Monkey leptin was measured in serum by a
kit purchased from Linco Research, Inc. (St. Charles, MO),
with an assay sensitivity of 0.5 ng/ml, and the intra- and interassay
variations were 1.6% and 2.3%, respectively.
Statistical analysis
Longitudinal differences within groups were analyzed by ANOVA
with post-hoc testing using the Student-Newman-Keuls
multiple range test. Cross-sectional differences between control and
ALC-treated groups were assessed by Student’s t test. The
tests were conducted using INSTAT software (GraphPad Software, Inc., San Diego, CA). P < 0.05 was considered
statistically significant.
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Results
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The dose of 2 g ALC/kg administered each afternoon produced a
mean ± SEM blood ALC concentration of 158.1 ±
8.8 mg/dl 3 h after nasogastric intubation. At that time, the
monkeys appeared only mildly intoxicated. Throughout the course of the
study, appetite and food consumption were not altered by this dose of
ALC. Assessment of morning (AM) blood samples confirmed that by this
time there was little or no remaining ALC detectable. Body weights were
not different (P > 0.05) between control and
ALC-treated monkeys whether comparing either mean monthly weights in
kilograms (Fig. 1
) or the percent
increase from their respective beginning weights (control, 24.5 ±
2.4%; ALC, 19.3 ± 2.9%).
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Figure 1. Effect of chronic ALC exposure on body weight.
Note that monthly weight gains were not different between control (CON)
and ALC-treated monkeys.
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Figure 2 demonstrates that there were no
significant differences in the starting levels of any of the hormones
measured, as determined by averaging the daily AM and evening (PM)
concentrations of each hormone, then expressing them as a mean ±
SEM over 5 consecutive days. The levels of these hormones
were again measured at 24, 28, and 32 months after ALC or sucrose
administration for 4, 8, and 12 months, respectively. Assessing the
mean 5-day hormone levels at each of these time points showed a
suppression of GH in the ALC-treated monkeys compared with the controls
at both 28 (P < 0.05) and 32 (P <
0.05) months of age (Fig. 2A). The serum levels of IGF-I were also
suppressed compared with control values at 28 (P <
0.05) and 32 (P < 0.001) months of age (Fig. 2B).
Additionally, the IGF-I levels in the ALC-treated group at 32 months
were depressed (P < 0.05) compared with their own
levels at 20, 24, and 28 months. Although the levels of serum FSH were
not affected (Fig. 2C), the 5-day assessment revealed depressed
(P < 0.01) levels of serum LH from 24–32 months of
age in the ALC-treated monkeys compared with the controls (Fig. 2D).
Furthermore, lower (P < 0.05) LH levels were observed
in the ethanol-treated monkeys from 24–32 months of age compared with
their own levels at 20 months of age. The levels of serum
E2 in the ALC-treated monkeys were modestly
depressed (P < 0.05) at 28 months of age, but were
markedly suppressed (P < 0.001) by 32 months compared
with E2 levels in control monkeys (Fig. 2E). Even
at 32 months of age, serum E2 levels in
ALC-treated monkeys were not different from their own 20-month-old
starting levels. In contrast, by 32 months of age,
E2 levels in control monkeys were substantially
increased (P < 0.001) over their 20-month-old
levels (Fig. 2E). Serum leptin levels were not different between
ALC-treated and control monkeys at any of the time points assessed
(Fig. 2F).
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Figure 2. Effects of ALC on puberty-related hormones. Blood
samples were drawn daily from each monkey at 0830 h (AM) and
2030 h (PM) for 5 consecutive days. Hormones were measured in
serum, and the daily averages were recorded by combining the AM and PM
values from each monkey. These values were then used to determine the
monkey’s respective hormone level over the 5-day period. Each
point represents the mean ± SEM 5-day
hormone levels from ALC (n = 5) and CON (n = 5) monkeys
during the 20-, 24-, 28-, and 32-month sampling periods. A, GH levels
in the ALC-treated monkeys were suppressed compared with those in CON
at both 28 and 32 months. B, ALC caused a moderate suppression of IGF-I
at 28 months, followed by a marked decline by 32 months. Furthermore,
in the ALC-treated group, IGF-I levels at 32 months were below their 20
month starting levels. C and D, respectively, show that FSH levels were
not affected by ALC, but LH levels were reduced from 24–32 months of
age compared with CON levels and were lower at all time points compared
with the 20 month starting levels. E, E2 levels in CON
monkeys rose markedly between 28 and 32 months of age, but this did not
occur in ALC-treated monkeys, thus causing levels to be lower at 28 and
32 months of age. F, Leptin levels were not affected by ALC. *,
P < 0.05; **, P < 0.01; ***,
P < 0.001 (ALC vs. same month CON).
+, P < 0.05; ++, P < 0.001
(ALC or CON vs. own 20-month-old starting level).
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Because GH and LH are released in a diurnal fashion as puberty
approaches, the effects of ALC on the secretion of these hormones were
further assessed by comparing their AM levels with those in the PM. As
shown in Fig. 3A, the pattern of AM-low,
PM-high GH levels began developing only in the control monkeys by 28
months of age (earlier ages not shown). Although the GH levels at that
time were elevated each of the five evenings, only during one evening
were the levels significantly higher than the respective AM levels.
This pattern further developed by 32 months of age, when it was again
apparent that the GH levels rose each evening, with three of the five
evenings now showing significantly higher GH levels compared with their
respective AM levels (Fig. 3C). Contrasting with the controls,
ALC-treated monkeys did not show a pattern of elevated GH levels either
at 28 (Fig. 3B) or 32 (Fig. 3D) months of age. Expressing these data as
total (AM or PM) GH output for every 5-day period analyzed demonstrated
marked increases (P < 0.01) in serum GH levels in the
evenings at both 28 and 32 months of age in control, but not
ALC-treated, monkeys (Fig. 3, E and F, respectively). Importantly, this
developmental pattern of increased PM GH release as well as the ability
of ALC to block this event were also observed when each monkey was
evaluated individually and not as a group (not shown).
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Figure 3. Effect of ALC on the diurnal secretion of GH.
A–D, Serum GH from control (CON) and ALC-treated monkeys at 28 and 32
months of age. Bars represent the mean ±
SEM GH levels from both groups of monkeys with samples
taken at 0830 h (AM) and at 2030 h (PM) for each of the 5
consecutive days, as noted by the number under each set
of bars. The AM-low, PM-high pattern of GH
secretion began developing in CON monkeys by 28 months and was further
developed at 32 months. Note that ALC blocked this pattern of elevated
GH secretion in the PM from developing. E and F, These data are the
mean ± SEM of the combined 5-day AM and combined
5-day PM GH levels from CON and ALC-treated monkeys at both 28 and 32
months of age. Note that at both time points PM elevations in GH
occurred in the CON, but not the ALC-treated, monkeys. A and C: *,
P < 0.05 vs. same day AM levels; E
and F: **, P < 0.01 vs. respective
AM CON levels; +, P < 0.05 vs.
respective PM CON levels.
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In contrast to GH, serum LH levels in control animals were
statistically similar in the AM and PM of the entire period examined
(Fig. 4, A–D). ALC treatments suppressed
LH levels equally well at both times of the day, with the first
decrease (P < 0.01) being detected at 24 months of age
and the levels remaining suppressed at those levels throughout the
study (Fig. 4, A–D). Detailed analysis of daily serum LH levels for
each group revealed the occurrence of small, sporadic increases in some
of the PM values during the 5-day sampling period. These developing
increases in LH secretion are best shown by calculating the mean
± SEM change in PM over AM levels for the 5
days. Figure 4E demonstrates that at 28 months of age, the magnitude of
these evening increases was similar in both groups (controls, 0.7
± 0.06 ng/ml; ALC, 0.9 ± 0.15 ng/ml). However, by 32 months of
age, the LH rise in the control monkeys had further increased in the PM
to 1.6 ± 0.2 ng/ml over that in the AM, whereas in the
ALC-treated monkeys, this PM increase was still approximately the same
level as that observed at 28 months (0.85 ± 0.1 ng/ml), now about
half that of controls (P < 0.01). Thus, ALC suppressed
not only basal LH values, but also the early developing increases in
evening LH levels that precede puberty. ALC consumption did not delay
menarche [controls, 24.5 ± 2.8 (n = 4); ALC-treated,
25.5 ± 1.2 (n = 4)]. One animal in each group had not
undergone menarche by the end of the study at 32 months of age. Figure 5 depicts the number of days between
menstruations in four control and four ethanol-treated monkeys during
the subsequent months after menarche. The monkeys receiving ALC showed
a longer (P < 0.05) interval between those periods of
menstruation than the control monkeys. Although we had limited samples
for progesterone analysis, the levels were low throughout the
experiment, and there were no signs of either corpora lutea or ablicans
upon histological inspection of the ovaries from all animals,
suggesting that none had reached ovulatory competency.
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Figure 4. Effect of ALC on the diurnal secretion of LH.
Blood samples were taken at 0830 h (AM) and 2030 h (PM) for 5
consecutive days. A–D, Serum LH levels from 20–32 months of age,
respectively. Bars represent the mean ±
SEM of the 5-day combined AM and the 5-day combined PM LH
levels from both control (CON) and ALC-treated monkeys. By 24 months of
age and continuing throughout the study, ALC caused the suppression of
LH equally well at both times of day. E, Effect of ALC on the
developing PM increase in the LH secretory pattern. Bars
represent the mean ± SEM increase ( ) in PM levels
over those levels observed in the AM for the 5-day sampling period.
Note that at 28 months, the PM increases were similar in both groups,
but at 32 months, these PM increases in the ALC-treated monkeys were
about half what was observed in the CON monkeys. *,
P < 0.05; **, P < 0.01
(vs. same month CON).
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Figure 5. Effect of ALC on menstrual patterns. The
developing intermenstruation intervals (mean number of days between
menstruations) are shown for four control (solid
symbols) and four ALC-treated (open symbols)
monkeys during subsequent months after menarche. All but two intervals
were below 40 days in the controls, whereas all but three intervals
were above 50 days in the ALC-treated animals. Note that two of the
ALC-treated animals showed intervals between menstruations in excess of
140 days. The inset depicts the mean ±
SEM intervals between menstruations for each group. The
double horizontal lines show the
mean ± SEM adult menstrual pattern for 20 rhesus
monkeys in the ORPRC colony. *, P < 0.05.
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Discussion
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For several years physicians have been aware of the possibility
that ALC may alter the developing neuroendocrine system; however,
despite this awareness very little is actually known of the effects of
ALC ingestion on puberty-related hormones and the progression of the
pubertal process. It is known that even after 2 weeks of abstinence,
ALC caused depressed estrogen levels in adolescent girls ranging from
12–18 yr of age (7). Also, ALC has been shown to cause depressed
testosterone and LH levels in adolescent, midpubertal boys (6).
Although limited, those important studies in humans provided the
initial evidence for the effects of ALC during pubertal development. In
the present study, we have used prepubescent female rhesus monkeys as
an animal model to assess in more detail the chronic effects of ALC on
adolescent neuroendocrine development. Our study is the first to show
that ALC ingestion lowers prepubertal circulating levels of GH, IGF-I,
LH, and E2 compared with control values.
Furthermore, although the age at first menstruation was not affected,
the interval between subsequent menstruations was lengthened
significantly, showing that ALC alters the development of a regular
monthly pattern of menstruation.
The low dose of ALC used in this study produced only moderate blood ALC
levels for a short period of time in the afternoon before declining and
did not significantly alter the monkeys’ food consumption or
weight gain throughout the experiment. The fact that growth rates were
not altered further suggests that this dose of ALC did not interfere
markedly with appetite and metabolism. Furthermore, the levels of serum
leptin, a peptide known for its role in controlling appetite, were
unchanged by ALC. Our results do not, however, rule out the possibility
that ALC may alter leptin or an action of leptin at a later time in
pubertal development, as the drug has recently been shown to lower
serum leptin during late juvenile development in female rats (13). The
levels of GH were slightly lower by 24 months of age in the ALC-treated
monkeys and were significantly depressed at 28 and 32 months. These
depressions were associated with the absence of the expected increase
in GH secretion at night between 28 and 32 months of age, which did
occur in the control monkeys. Similar to what we have seen in rats
(14), the ALC-induced depression in GH secretion was paralleled by a
similar depression in IGF-I. Hence, as these monkeys were well
nourished, it is likely that the suppressed circulating levels of IGF-I
contributed to the slightly lower body weights observed in the
ALC-treated monkeys. Although the mechanism of an ALC-induced
depression in this peptide is not known, it could be due to depressed
GH, an alteration in the synthesis or affinity of the GH receptor, or a
direct effect on the hepatocyte to block IGF-I synthesis or
processing.
The fact that ALC caused depressed levels of serum LH without affecting
FSH is not surprising, because we have previously reported this
differential effect on gonadotropin secretion in prepubertal female
rats (4, 5, 15). Although the mechanism of this action is not known, it
is possible that ALC can detrimentally affect the neurons producing
LHRH in the hypothalamus, but not affect those neurons producing
the proposed FSH-releasing hormone. With regard to LH, the
serum levels were suppressed in the ALC-treated monkeys from 24–32
months of age. Interestingly, in contrast to the effect on GH, the ALC
treatments suppressed LH levels equally well during both the AM and PM
hours. It is known that increases in LH values in the PM are pivotal
for the progression of the mammalian pubertal process (16). We first
noted small sporadic PM increases in LH levels in both control and
ALC-treated monkeys at 28 months of age, with these evening increases
being similar in both groups; however, by 32 months of age the
magnitude of these evening increases in ALC-treated monkeys were less
than half that in the controls and, in fact, were not greater than the
elevations observed at 28 months. Also, the control monkeys showed the
expected developmental increase in serum E2
levels, which did not occur in the monkeys receiving ALC. Thus, we
suggest that the ability of ALC to suppress the developing increases in
LH and E2 contributes to this drug’s action to
lengthen the time between menstruations, hence altering significantly
the development of a normal, regular monthly menstrual pattern.
Recent evidence supporting the hypothesis that IGF-I is a metabolic
signal capable of acting centrally to influence the pubertal process
warrants discussion, because it may provide insight into the mechanism
by which ALC affects LH secretion. It has been known for several years
that circulating levels of IGF-I increase markedly during pubertal
development (17, 18, 19). We have shown using the rat that IGF-I stimulates
LHRH secretion form the female median eminence incubated in
vitro (20). Furthermore, we showed IGF-I derived from peripheral
sources is capable of acting centrally to induce LH release and that
the central administration of IGF-I can advance female puberty in the
rat (21). Subsequently, it was reported that the premature elevation of
serum IGF-I levels advanced first ovulation in rhesus monkeys, an
action resulting from increased LHRH neuronal activity (22).
Furthermore, it has very recently been shown that IGF-I replacement can
advance puberty in GH receptor knockout mice (23). Taken together,
there is now compelling evidence in both rodents and primates that
IGF-I plays an important role in linking somatic development to the
activation of the LHRH/LH-releasing system and the acquisition of
female puberty. We suggest that increased LH levels during pubertal
development are due at least in part to rising levels of IGF-I crossing
the blood-brain barrier at the median eminence and facilitating LHRH
release. Importantly, we have shown here that between 28 and 32 months
of age, ALC caused a dramatic decrease in serum IGF-I levels, which was
associated with a further suppression of LH. Furthermore, during this
period, these actions were associated with the lack of a significant
increase in serum E2 levels and the noted
prolonged interval between menstruations in ALC-treated monkeys.
Although the mechanism of action by which ALC alters serum IGF-I is not
known, it seems plausible that the reduced levels of IGF-I caused by
ALC are insufficient to stimulate the LHRH release typically associated
with the PM increases in LH secretion at this time of development. Our
data showing the ALC-induced reduction in the PM increases in LH at
this time support this action.
In summary, our results are the first to demonstrate significant
detrimental effects of low dose ALC exposure on the activation of
critical puberty-related hormones in female rhesus monkeys.
Furthermore, we showed that even though the age at first menstruation
was not altered, the drug did significantly alter the development of a
regular monthly pattern of menstrual activity. Although important
follow-up studies are needed, the present results suggest that human
adolescents and teenagers consuming moderate amounts of ALC are at risk
for alterations in growth and the normal timing of puberty.
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Acknowledgments
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We thank Sam Siemon, Tonya Swanson, Donald Ediger, Douglas Barr,
Dennis Grund, Shirley Trogdon, and the other members of the Division of
Animal Resources, ORPRC, for their professional care and husbandry of
the animals used in this study.
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Footnotes
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1 This work was supported by NIH Grants AA-07216, AA-00104, ES-09106,
and RR-0016. 
Received September 24, 1999.
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G. A. Dissen, R. K. Dearth, H. M. Scott, S. R. Ojeda, and W. L. Dees
Alcohol Alters Luteinizing Hormone Secretion in Immature Female Rhesus Monkeys by a Hypothalamic Action
Endocrinology,
October 1, 2004;
145(10):
4558 - 4564.
[Abstract]
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Abstract
Introduction
