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Estradiol increases somatomedin-C concentrations in adolescent rhesus macaques (Macaca mulatta).

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American Journal of Primatology 11:53-62 (1986)
Estradiol Increases Somatomedin-C Concentrations in
Adolescent Rhesus Macaques (Macaca mulatta)
ERIN L. OSTERUD, SUZETTE LACKEY, AND MARK E. WILSON
Yerkes Regional Primate Research Center ofEmory University, Field Station, Lawrenceuille,
Georgia
Estradiol (E2) may enhance somatomedin-C(Sm-C)secretion during puberty
in female rhesus monkeys. The present study evaluated the importance of
age and acute changes in E2 on Sm-C secretion. Intact (INT) females at
their first ovulation (age 3.5 yr; n = 6) had higher levels of Sm-C across the
ovulatory cycle than did intact adults (ADT) (n = 5). Levels of Sm-C were
similar for both groups during the follicular and luteal phases despite
higher follicular phase levels of E2. Young, ovariectomized, E2-treated
(EBOVX)females (age 3.5 yr; n = 5; E2 = 50 pg/ml) had higher basal levels
of Sm-C than did either age-matched ovariectomized (OVX) females (n = 3),
ovariectomized adults (OXA), or E2-treated ovariectomized adults (E2A)(E2
= 100 pg/ml). When ovariectomized groups were given E2 to induce ovulatory increases, no changes in serum Sm-C occurred. Comparisons among
age-mates revealed that basal levels of Sm-C were similar between INT and
EBOVX, yet these levels were higher than those for OVX. Sm-C levels were
similar among all adult groups. Serum growth hormone (GH) was highest
in EBOVX, next highest in INT and OVX, and lowest in all adults. Higher
Sm-C levels in young animals are, thus, related to these age differences in
GH concentrations and are further enhanced by basal levels of E2 and not
by acute changes in this steroid. Low Sm-C secretion in adults is associated
with low GH levels. Thus, the facilitory effect of basal E2 on Sm-C release
is observed during conditions when basal GH levels are elevated, a situation
normally limited to adolescence.
Key words: growth hormone, maturation
INTRODUCTION
In addition to their role in growth and development of sex organs and secondary
sexual characteristics, estrogens may also be involved with overall body growth
[Tanner, 19621. The mechanisms by which estrogens are responsible for this latter
effect are poorly understood. Previous studies have shown that estradiol (E2) enhances somatomedin-C (Sm-C) secretion in children [Cuttler et al, 19851, adult
baboons [Copeland et al, 19841, and immature rhesus monkeys [Wilson et al, 19841.
Estradiol may have a maximal effect on Sm-C secretion in the presence of elevated
Received October 18, 1985; revision accepted March 7,1986.
Address reprint requests to Mark E. Wilson, Yerkes Regional Primate Research Center of Emory
University, Field Station, 2409 Collins Hill Road, Lawrenceville, GA 30245.
0 1986 Alan R. Liss, Inc.
54 I Osterud, Lackey, and Wilson
levels of growth hormone [Wilson et al, 19841. Female patients with gonadal dysgenesis, and therefore chronic estrogen deficiency, fail to show the pubertal rise in SmC unless treated with endogenous estrogen [Cuttler et al, 19851. In contrast, neither
estrogen nor testosterone increases Sm-C levels in adult humans [Meyer et al, 19821.
Furthermore, somatomedin-C levels increase at the time of puberty in chimpanzees;
these increases, however, are not necessarily related to E2 changes but may be
related to other gonadal and adrenal steroid production [Copeland et al, 19851. The
present study was designed to evaluate how basal and acute changes in E2 influence
levels of somatomedin-C in adolescent and fully adult female rhesus monkeys.
MATERIALS AND METHODS
Subjects
Six sets of female rhesus monkeys (Mucuca rnulatta) were subjects: (1)intact
postpubertal (INTI (n = 6); (2) ovariectomized, E2-treated postpubertal (E2OVX) (n
= 5); (3) ovariectomized postpubertal (OVX) (n = 3); (4) intact adult (ADT) (n = 5);
(5) ovariectomized, E2-treated adult (E2A ‘ 3 = 4); and (6) ovariectomized adult
(OXA) (n = 4). Of ‘he postpubertal females, all were 3.5 yr of age and were studied
a t their first ovulation (IN5J and during the period of significant increases in serum
luteinizing hormone concentrations [E20VX and OVX; Wilson et al, 19861. Thus,
these females were reproductively mature but were not yet fully grown. Adult
females were all >6.5 yr of age. Subjects were housed in outdoor compounds as
previously described [Walker et al, 19821. The analysis for the ovariectomized adults
was done post hoc, as physiological samples for these animals were initially collected
to assess the effects of E2 on female sexual behavior (samples provided by Dr. K.
Wallen). Animals were fed commercial monkey chow twice a day with a supplement
of fresh fruit daily. Sufficient food was available at both feedings to ensure that all
animals ate to satiety.
Procedures
Intact adults were studied during late summer and fall of 1983. All other
subjects during late summer and fall of 1984. Females were ovariectomized under
ketamine hydrochloride anesthesia. Ovariectomies were performed on postpubertal
subjects when they were 12 mo of age and on adults 1 yr prior to the study.
Ovariectomized females were randomly chosen to receive a capsule containing
estradiol 17-@.Capsule construction followed the procedure previously described
[Wilson et al, 19841. Capsules were filled with 8-10 mm estradiol for postpubertal
females, 30 mm estradiol for adults, or left empty depending on treatment group.
Estradiol capsules were constructed to maintain serum concentrations at postmenarchial levels ( 50 pg/ml) in young females and midfollicular phase levels (100 pg/
ml) in adult females. Capsules were implanted subcutaneously in the subscapular
region under ketamine hydrochloride.
The effects of basal levels of E2 on Sm-C and GH secretion were assessed in
gonadally intact and ovariectomized untreated or E2-treated females in late summerlearly fall (August-September) prior to the onset of ovulatory cycles and the
initiation of the annual breeding season. Basal levels of E2, Sm-C, and GH were
determined from samples collected twice weekly from intact females, and weekly
from ovariectomized females. All animals had been habituated to the procedure to
minimize any stress-induced hormone changes [Blank et al, 19831. The effects of
acute changes in E2 on Sm-C and GH secretion were assessed across a n ovulatory
cycle in intact females, encompassing 16 days prior to and 8 days after ovulation.
The acute effects of E2 on Sm-C and GH in ovariectomized females was measured in
-
Estradiol Increases Somatomedin-C / 55
response to a bolus injection of E2. Estradiol benzoate was administered in oil (50
pgkg) and resulted in serum concentrations > 300 pg/ml at +24 hr. Blood samples
were collected at -24, 0, +24, +48, and +72 hr relative to the injection. All blood
samples were collected, as described previously [Walker et al, 19821, from unanesthetized animals via the saphenous vein. Ovulations in intact females were confirmed by significant and sustained levels of serum progesterone [Walker et al,
19831.
Radioimmunoassay
Levels of Sm-C were quantified by double antibody radioimmunoassay following
the procedure described by Copeland et a1 [1983]. First antibody and tracer were
provided through the National Hormone and Pituitary Program of NIH by Drs. L.E.
Underwood and J.J. Van Wyk of the University of North Carolina. Anti-Sm-C serum
(AS-6) was raised in rabbits against human Sm-C and has been characterized
previously [Furlanetto et al, 19771. Iodinated human Sm-C, having a specific activity
of 325 pCi/mg, was used as a tracer. The standard (YS-1)was a pool of normal adult
human serum. This standard was validated against a commercially prepared pool of
adult serum (Ortho 1778-5) kindly provided by Drs. Underwood and Van Wyk. All
results are expressed as U/ml of YS-1, assuming 1unit per ml of serum.
Assays were performed in 12 x 75-mm polystyrene culture tubes (Lancer). The
assay buffer (pH 7.5) was 0.03 M phosphate with 0.02% protamine sulfate (grade X),
0.25% BSA, 0.2% sodium azide, and 0.01 M ethylenediamine tetraacetic acid (EDTA).
Standards were added in the range of .13-15.0 p1 of serum and adjusted to a volume
of 300 p1 with assay buffer. Anti-Sm-C serum was added in 50 p1 of a 1:2,000 dilution.
Approximately 10,000 cpm of 1251Sm-C was added in 150 pl to each tube. Separation
of bound from free hormone was achieved by double antibody, yielding a final
volume of 700 p1 tube. Antibody and standard or unknown were incubated at 4°C
for 1 h r before the addition of the tracer. Following incubation overnight (16 hr) at
4"C,second antibody and normal rabbit serum were added. After additional incubation at 4°C for 16-24 hr, samples were centrifuged a t 3,000 RPM for 30 min, and
resulting pellets were counted in a Micromedic Gamma Counter. Interassay coefficient of variation was 2.4%. Intrassay coefficients of variation were 13.6% and 9.3%
for acid-treated rhesus serum and human acromegalic serum, respectively.
Binding proteins in monkey serum were eliminated by treatment of serum with
0.2 M glycine HC1 buffer (pH 3.2). A 100-p1 aliquot of acid buffer and a n equal
volume of serum were gassed with N2, capped, and incubated at 37°C for either 1hr
or 48 hr. This sample was then stored at -20 C until assay. Assay buffer was added
to these acidified samples, as well a s native serum and EDTA plasma, for a final
dilution of 1:lOO for assay.
The log dose-response curves for the human standards and rhesus serum preparations are shown in Figure 1. As can be seen, all materials were parallel to one
another. For the YS-1 standard, the correlation between the mean log dose and mean
B/Bo (n = 9 assays) was r = -0.996 with a slope of -2.6 and a Y-intercept of 1.5.
Assuming the Ortho standard 1778-5 has a potency of 1.0 U/ml [Copeland et al,
19831, the YS-1 standard was estimated to have a potency of 1.14 U/ml. Furthermore,
a comparison of YS-1 containing 3.75 mg EDTMml and YS-1 with no EDTA yielded
parallel lines with similar slopes (-2.5 and -2.6, respectively). All data are thus
expressed as units of YS-1 per ml of serum.
Untreated juvenile rhesus serum exhibited more displacement than did the
human YS-1 standard but less than that observed in human Acromegalic serum.
Displacement at B/Bo = 50%was 0.66 pl for native rhesus serum and 1.70 pl for YS1but was only 0.40 p l for Acromegalic serum (kindly provided by Dr. E.M. Spencer,
56 I Osterud, Lackey, and Wilson
I
.05
.20
.40
I
1.0
5.0
10.0
PI
Fig. 1. Log dose-response curves of human serum standards YS-1(-0-1
and Ortho 1778-5 (-O-),human
acromegalic serum (-0.)
native rhesus serum [-A-),
and acidified rhesus serum (-A-)
a s measured in the
Sm-C RIA.
TABLE I. Estimates of Sm-C (Ulml) Using Four Different Sample Preparations
Animal
Lv
Gu
Iw
Iv
ZU
x
(+
SE)
EDTA
ulasma
Native
serum
3.4
1.4
1.4
0.8
0.8
1.6
(0.5)
4.6
1.6
2.6
1.5
1.1
2.3
(6)
Acid-treated serum
lhr
48 hr
6.6
2.3
1.2
1.2
1.2
2.5
(1.0)
24.9
7.8
8.5
11.6
5.9
11.7
(3.4)
Childrens Hospital, San Francisco). Rhesus serum treated with acid for 48 hr
exhibited the greatest displacement, with 0.17 pl binding at 50% with respect to
reference.
A direct comparison of different preparations of rhesus samples (Table I) revealed that serum incubated with equal volumes of glycine-HC1buffer for 48 hr
yielded significantly higher levels of immunoreactive Sm-C than did either 1-hr
= 15.5; Newman-Kuels
acid-treated serum, native serum, or EDTA plasma (F~,JG
post hoc tests, P <.05). There were no differences in Sm-C values among the
remaining preparations (Newman-Kuelspost hoc tests, P > .05). Indeed, estimates
of Sm-C were 433 f 71.5% greater in 48-hr acid-treated samples as compared to
untreated serum. Despite these quantitative differences, correlations were significant (df = 3, P < .05) between values from 48-hr acid-treated serum and 1-hr treated
serum (r = 0.93), untreated serum (r = 0.91), and EDTA plasma (r = 0.90). Given
these findings, all subsequent assays were performed on 48-hr acid-treated samples.
Estradiol Increases Somatomedin-C / 57
=
E
20.0-
\
2
0
E
v)
10.0-
0
24
48
Hours from Treatment
Fig. 2. Mean Sm-C levels in acidified rhesus serum following treatment (time 0) with 0.2 IUAg of hGH.
Shaded area represents f SE.
In order to assess changes in immunoassayable Sm-C in response to GH, five
prepubertal male rhesus macaques (31.7 & 0.3 mo of age) were treated with 0.2 IU/
kg of hGH (IM), and blood was drawn a t 0, +12, +18, +24, and 48 hr.Immunoreactive levels of Sm-C rose significantly following treatment (Fig. 2). Serum concentrations were significantly higher a t +12 hr and remained so through +24 h r before
falling back to baseline values (F4,16 = 3.22; Newman-Kuels tests, P < .05). Peak
levels a t + 12 hr rose 88.8 & 33.1% over baseline following hGH treatment.
Concentrations of GH were determined by hGH double antibody RIA employing
a procedure previously described [Friesen & Carr, 19761. Highly purified hGH was
used for iodination and hGH, having a potency of 2.2 IU NIH HS 2919G/mg, was
used as the standard. The antibody to hGH (B-7)was generated in rabbits and was
used at a final dilution of 1:250,000. As illustrated in Figure 3, purified macaque
gonadotropins, follicle-stimulating hormone (FSH), and cyn luteinizing hormone
(LH), showed no cross-reactivity with the antibody. Purified human prolactin (hPRL)
exhibited slight displacement at high concentrations. Human placental lactogen
showed some cross-reactivity (4.4% at 50%B/Bo). Only rhesus serum was parallel to
the hGH standard. Intra- and interassay coefficients of variation averaged < 3%and
13.9%, respectively.
Serum concentrations of E2 were determined by RIA having a sensitivity of 2.0
pg/tube [Wright et al, 19731. To confirm ovulation, serum progesterone was measured by a previously validated RIA having a sensitivity of 5 pg/tube [Wilson e t al,
19821. Coefficients of variation for the steroid assays were < 10%.
Statistical Analysis
All grouped data were expressed as 8 & SEM. Longitudinal hormonal changes
were evaluated with ANOVA models with repeated measures on mean values for
each individual a t each treatment phase. Specific differences among treatment
groups were evaluated with Newman-Kuels tests [N-K tests, Keppel, 19731. For
statistical comparisons, the ovulatory cycle was subdivided into six equal phases of
58 I Osterud, Lackey, and Wilson
FSH
I ,
.01
.05
2b4bl
1
1
1
25
.5
1.0
I
1
10.0 20.0
ngJtube
PI
Fig. 3. Log dose-response curves of hGH and other biologically relevant proteins, as well as native rhesus
serum, as measured in the hGH RIA.
4 days each encompassing the follicular (days - 16 through - 12), periovulatory
(days -11 through day 01, and luteal phases (days +1through +8). All statistical
values of P < .05 were considered significant.
RESULTS
As illustrated in Figure 4, basal levels of E2 enhanced Sm-C secretion only in
adolescent females. Somatomedin-C levels were significantly higher in INT and
E2OVX than in OVX or any of the three adult groups (F5,21 = 11.73, P < .05, NK
tests). Levels of Sm-C were not different among the OVX and all of the adult groups.
Basal concentrations of E2 were similar in INT (54.5 f 3.8 pg/ml), E2OVX (51.0 f
2.8 pg/ml), and ADT (49.0 f 3.2 pg/ml), yet all were significantly lower than those
of E-2-treated ovariectomized adults (E2A = 112.7 20.6 pg/ml; F3,16 = 10.92, P <
.05, N-K tests). Serum concentrations of E2 in both ovariectomized untreated groups
were below the sensitivity of the assay (<38 pg/ml).
Acute changes in serum E2 did not influence levels of Sm-C in either age group.
Although INT females had significantly higher levels of Sm-C throughout a n ovulatory cycle than did ADT females (Fig. 5; F1,g = 36.28, P < .05), levels of Sm-C did
not vary at different stages of the cycle in either age group (F1,g = 2.58, P < .05).
Changes in serum E2 were similar across the cycles of both INT and ADT females
(F1,g = 3.79, P > .05). Somatomedin-C levels remained unchanged despite significant fluctuations in serum E2 (pg/ml: follicular = 92.6 f 15.2; 107.2 f 12.1; periovulatory = 115.4 f 8.7; 254.6 f 28.6; luteal = 69.9
8.1; 114.1 k 15.8; F5,45 =
23.99, P < .05).
Administration of a bolus injection of E2 to ovariectomized females also failed
to increase serum concentrations of Sm-C above baseline values (Fig. 6) in either
age group. Levels of Sm-C were significantly higher in E20VX than in OVX and
E2A, which were similar to one another (Fz,ll = 47.36, P < .05, N-K tests). In all
groups, Sm-C concentrations were not different from baseline for 72 hr following the
injection of E2 (F4,34 = 1.24, P > .05). Baseline levels of serum E2 were 51.0 k 2.8
+
+
Estradiol Increases Somatomedin-C I 59
INT E,OVX
OVX
€PA
ADT
Post-Pubertal
OXA
Adults
Fig. 4. Mean (k SE) levels of Sm-C as a function of age group and gonadal status prior to the onset of the
annual breeding season.
I
I
I
I
0 INT
I
Luteal Phase
a AD1
zol
10
LL
Follicular Phase
I
Peri-Ovulatory Phase
Ovulation
Fig. 5. Changes in X = SE levels of Sm-C at three phases of an ovulatory cycle in adolescent (INTI and
adult females (ADT). Each block represents the average of value of 4 days.
pg/ml for E20VX, 112.7 & 20.6 pg/ml for E2A, and <38 pg/ml for OVX. Twentyfour hours following the injection of E2, serum concentrations between 300-800 pg/
ml were achieved.
During the study period, serum levels of GH also varied with age (F5,21= 9.61,
P < .05). Basal levels of GH were significantly higher in E2OVX (34.6 t- 7.7 ng/ml)
than in INT (18.2 & 2.5 ng/ml). Basal levels of GH in INT, in turn, were significantly
higher than in OVX females (11.8 k 2.5 ng/ml). Levels for all three adult groups
were similar to one another and were significantly lower than in adolescent groups
(ADT: 5.3 + 0.8 ng/ml; E2A: 5.1 & 1.1ng/ml; OXA: 4.5 f 1.2 ng/ml).
60 I Osterud, Lackey and Wilson
M E,OVX
M ovx
M E,A
T
I
Baseline
I
t24
I
+48
+72
E, Challenge/Time Course
Fig. 6. Sm-C levels (X = SE) in adolescent and adult ovariectomized females in response to a bolus
injection of E2-benzoate.
DISCUSSION
The results of the present study indicate that estradiol enhances Sm-C secretion
in the presence of GH in postpubertal, female rhesus macaques. Gonadally intact
and ovariectomized, estradiol-treated, postpubertal females had significantly higher
basal levels of somatomedin-C than did ovariectomized age-mates and all adult
groups regardless of gonadal status. However, Sm-C levels were not affected by
acute changes in estradiol during the follicular and luteal phases or following the
administration of E2 to mimic the ovulatory midcycle surge in either postpubertal
or fully adult groups. Basal levels of GH were significantly higher in all postpubertal
groups as compared with adult females. These age differences in basal GH levels
confirm earlier reports of maturational increases in basal GH secretion in female
monkeys [Wilson et al, 1986; Wilson et al, 19851. Furthermore, the absolute levels
of GH attained in the adolescent females varied as a function of gonadal status.
Highest levels of serum GH were exhibited by E2-treated ovariectomized adolescent
females followed by intact adolescent females. In contrast, lowest levels of GH in
adolescents were found in the untreated ovariectomized group, in which the levels
were, nevertheless, higher than those found in adults.
These data suggest that basal levels of E2, possibly mediated by increases in
GH, enhance Sm-C secretion in animals who are reproductively mature but have
not completed physical growth. The lack of an effect of E2 on Sm-C secretion in
adult female monkeys is similar to that observed in human adults [Meyer et al,
19821. Female rhesus macaques do not attain physical maturity until approximately
7 years of age [van Wagenen & Catchpole, 19561, some 3.5 years beyond the age of
the adolescent animals in the present study. The E2-induced increases in Sm-C in
adolescent monkeys were associated with significantly higher levels of GH. Testosterone administration elevates Sm-C levels in boys with normal GH profiles but not
in those whose GH concentrations are reduced [Parker et al, 19841. Furthermore,
treatment of precocious children with an LHRH agonist not only lowers serum sex
steroid and Sm-C levels but also GH concentrations [Harris et al, 19851. Facilitory
effects of estrogens on GH secretion have been observed in children [Merimee &
Fineberg, 19711 as well as in adult humans [Frantz & Rabkin, 19651 and baboons
Estradiol Increases Somatomedin-C I 61
[Copeland et al, 19841. In contrast, basal levels of E2 were associated with higher
GH levels only in adolescent monkeys in the present analysis. Furthermore, GH
levels in prepubertal, E2-treated ovariectomized monkeys were higher than in intact
animals despite the measurable quantities of E2, suggesting that some factor from
the premenarchial ovary may dampen GH secretion even in the presence of E2
[Wilson et al, 19841. Age may thus be a critical factor in determining the effect of
E2 on both GH and Sm-C secretion. As long as GH levels are somewhat elevated.
E2-associated increases in Sm-C secretion are observed despite differences in the
absolute magnitude of GH concentrations [Wilson et al, 19841.
Although ovariectomized, untreated adolescent females had higher basal GH
levels than did any of the adult groups, Sm-C concentrations were similar. Somatomedin-C levels do show a slight age-dependent rise in ovariectomized females [Wilson et al, 1984; Wilson et al, 19851, but the full maturational increase may be
dependent upon the presence of E2 [Cuttler et al, 19851. Thus, E2 may not only act
to increase Sm-C levels indirectly via GH secretion but also to directly influence
Sm-C release. Whether the limitation of this facilitory affect of E2 to young monkeys
is due to age-dependent reductions in GH secretion following the completion of
growth or to changes in Sm-C secretory capacity is unknown. Furthermore, the SmC values reported in this study represent “total” serum Sm-C. Although the correlation between total (acid-treated serum) and free (untreated, natural serum) Sm-C
was significant, the biological differences and, thus, the significance between the
two are not fully appreciated. Also, treatment of pharmacological levels of E2 does
alter binding of Sm-C to serum proteins, thus affecting the availability of free Sm-C
[Copeland et al, 19841. It is not known how these binding proteins change throughout
reproductive development as circulating levels of estradiol vary. Thus, although E2
may directly or indirectly increase Sm-C secretion, concomitant modulation of the
serum binding proteins may affect the biological activity of circulating concentrations. This complex relationship between reproductive onset, the control of Sm-C
secretion, and subsequent growth awaits further elucidation.
CONCLUSIONS
1. Basal levels of E2 enhanced Sm-C secretion in adolescent but not in adult
female rhesus macaques.
2. Acute changes in E2 did not influence Sm-C levels in either adolescent or
adult females.
3. Increased concentrations of Sm-C by E2 were associated with age-related
differences in basal levels of serum GH.
4. Higher concentrations of GH observed in adolescent monkeys may be further
enhanced by developmental increases in E2.
ACKNOWLEDGMENTS
We wish to thank M.A. Smith for her technical assistance and L. Wright for her
editorial assistance. We also thank the National Pituitary Agency and Drs. L.
Underwood and J. van Wyk (University of North Carolina) for the reagents for the
Sm-C assay, and H. Friesen (University of Manitoba) for the reagents for the GH
assay. The cyn LH, cyn FSH, hPRL, human placental lactogen, and the hGH for SmC induction were kindly provided by the National Pituitary Agency. Determinations
of Sm-C and GH were done in the Yerkes RIA facility, and those of E2 and progesterone were done in the Endocrine Research Lab, VA Medical Center (Decatur, GA).
This investigation was supported by HD 16305, HD 18120 and in part by NIH grant
RR-00165. The Yerkes Center is fully accredited by the American Association for
the Accreditation of Laboratory Animal Care (AAALAC).
62 I Osterud, Lackey and Wilson
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estradiol, increase, macaque, concentrations, rhesus, somatomedin, adolescenta, mulatta, macaca
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