You are on page 1of 10

This article was downloaded by: [TÜBTAK EKUAL]

On: 13 April 2009


Access details: Access Details: [subscription number 772814176]
Publisher Informa Healthcare
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK

International Journal of Neuroscience


Publication details, including instructions for authors and subscription information:
http://www.informaworld.com/smpp/title~content=t713644851

SEXUAL DIMORPHISM IN RELATIONS OF BLOOD GROWTH-HORMONE


LEVELS TO BODY AND BRAIN WEIGHTS IN NEWBORN RATS
Derya Deniz Elalmis a; Uner Tan b
a
Medical School, Department of Physiology, Erciyes University, Kayseri, Turkey b Faculty of Sciences,
Department of Physics, Cukurova University, Adana, Turkey

Online Publication Date: 01 December 2007

To cite this Article Elalmis, Derya Deniz and Tan, Uner(2007)'SEXUAL DIMORPHISM IN RELATIONS OF BLOOD GROWTH-
HORMONE LEVELS TO BODY AND BRAIN WEIGHTS IN NEWBORN RATS',International Journal of Neuroscience,117:12,1747 —
1755
To link to this Article: DOI: 10.1080/00207450701592964
URL: http://dx.doi.org/10.1080/00207450701592964

PLEASE SCROLL DOWN FOR ARTICLE

Full terms and conditions of use: http://www.informaworld.com/terms-and-conditions-of-access.pdf

This article may be used for research, teaching and private study purposes. Any substantial or
systematic reproduction, re-distribution, re-selling, loan or sub-licensing, systematic supply or
distribution in any form to anyone is expressly forbidden.

The publisher does not give any warranty express or implied or make any representation that the contents
will be complete or accurate or up to date. The accuracy of any instructions, formulae and drug doses
should be independently verified with primary sources. The publisher shall not be liable for any loss,
actions, claims, proceedings, demand or costs or damages whatsoever or howsoever caused arising directly
or indirectly in connection with or arising out of the use of this material.
Intern. J. Neuroscience, 117:1747–1755, 2007
Copyright  C 2007 Informa Healthcare USA, Inc.

ISSN: 0020-7454 / 1543-5245 online


DOI: 10.1080/00207450701592964

SEXUAL DIMORPHISM IN RELATIONS OF BLOOD


GROWTH-HORMONE LEVELS TO BODY AND
BRAIN WEIGHTS IN NEWBORN RATS

DERYA DENIZ ELALMIS


Downloaded By: [TÜBTAK EKUAL] At: 07:11 13 April 2009

Erciyes University
Medical School, Department of Physiology
Kayseri, Turkey

UNER TAN
Cukurova University
Faculty of Sciences, Department of Physics
Adana, Turkey

The growth promoting effects of growth hormone (GH) are well-known. How-
ever, the studies in this respect did not consider the sexual dimorphism. The
adverse—growth limiting—GH effects were also reported in human newborns (see
Tan, 1992, 1995; Tan et al., 1998). A similar study was replicated in the newborn
rat pups in the present work. The serum GH level, body weight, body height, right-
and left-brain weights were measured just after birth in rat pups. The relations of the
serum GH levels to the bodily measurements were found to be sexually dimorphic.
Namely, there were no significant correlations between the serum GH levels and
the body size (weight and height) in males, whereas there were inverse relations
between these parameters in females. The GH level negatively linearly related to
the right-, left-, and right- minus left-brain weights in females, whereas only the
right-brain weight positively linearly correlated with the serum GH level, the right-
minus left-brain weight being also positively linearly correlated with the serum GH
level in males. The results suggested that the sexual dimorphism should be taken
into consideration in studies concerning the global GH effects. The relation of the

Received 14 April 2007.


Address correspondence to Prof. Dr. Uner Tan, Cukurova University, Faculty of Sciences,
Department of Physics, 01330 Adana, Turkey. E-mail: unertan37@yahoo.com

1747
1748 D. D. ELALMIS AND U. TAN

serum GH level to the right-left brain asymmetry, also sexually dimorphic, suggests
a role of GH in cerebral lateralization.

Keywords body size, brain, female, growth hormone, male, rat

INTRODUCTION
The role of growth hormone (GH) in ontogeny has been only partially explained.
The GH dogma was that it has no role in fetal growth and development, based
on clinical studies. However, the GH receptors were found in prenatal mouse,
human, and cow during fetal development (e.g., Garcia-Aragon et al., 1992;
Hill et al., 1992). Accordingly, Tan (1992) has first provided evidence that GH
may affect the human central nervous system during prenatal development.
Downloaded By: [TÜBTAK EKUAL] At: 07:11 13 April 2009

Interestingly, contrary to the GH dogma, the grasp-reflex strength from the right
and left hands showed an inverse correlation with the umbilical hGH taken just
after the birth in female babies. In males, there was a direct correlation between
these variables as expected from the GH dogma.
Because of the inverse effects of the hGH on the primitive spinal reflex
activity found in female neonates, the possible associations of the hGH with
the bodily measurements were re-studied in human neonates (see Tan, 1995).
In contrast to the expected growth promoting GH effects, there was an inverse
correlation between the serum GH concentrations and the head circumference
in the male and female human neonates, suggesting a rate limiting effects of
the hGH on brain development. There was a sexual dimorphism concerning
the body weight: the inverse relationship between these two variables was
significant only for females, not for males.
To test a possible replication, the umbilical hGH in relation to bodily
measurements (height, weight, head circumference) was restudied, in relation
to T3 and free testosterone hormones in human neonates (see Tan et al., 1998).
Interestingly enough, the blood hGH concentration was found to be inversely
related to the neonatal height, weight, and head circumference, however, only
in females, not males, suggesting a sexual dimorphism in GH effects during
prenatal development.
The sexual dimorphism in the control of GH secretion and GH levels were
previously reported (Jansson et al., 1985; Geary et al., 2003), but not with
regard to its effects on brain and body development. GH was detected in rodent
brain as early as d 10 after gestation before its appearance in the fetal pituitary
(Hojvat et al., 1982). Consistent with the growth promoting effects of the GH
on fetal brain, the GHRH receptor-deficient little mouse exhibit small brain
and retarded neuronal growth (Noguchi, 1996). Furthermore, transgenic mice
GROWTH HORMONE 1749

over-expressing GH have spinal motoneurons and brains larger than normal (see
Chen et al., 1997). It has recently been shown that GH promotes proliferation
of neural precursors, neurogenesis, and gliogenesis during brain development
of fetal rats (Ajo et al., 2003). GHRs are evident in mouse and bovine preim-
plantation embryos (Kolle et al., 1998). Widespread distribution of GHR was
demonstrated in the mid–late gestation fetal rat (Garcia-Aragon et al., 1992).
The growth promoting role of GH in fetal development is frequently reported
in humans and animals (e.g., Danilovich et al., 1999; Kim et al., 1993). Spencer
et al. (1994) reported that pups were heavier in GH-treated rats than normal
rats; administration of GH to the mothers significantly increased the birth
weight. However, a possible sexual dimorphism in GH effects was not taken
into account in these studies. Considering the earlier reports with the prenatal
Downloaded By: [TÜBTAK EKUAL] At: 07:11 13 April 2009

growth-reducing effects of hGH on the brain–body development (see Tan, 1995;


Tan et al., 1998) exhibiting sexual dimorphism, the present study replicated the
relation of the fetal GH to the brain and body size in the newborn rats.

METHODS
Timed pregnant rats were individually housed in a room with controlled lighting
(12:12 h light/dark cycle), temperature, and humidity. Tap water and standard
rat chow were freely available. There were 36 female and 42 male pups,
which were weighed and their body- and tail-lengths were measured, and
killed by decapitation just after birth. Blood was taken from the heart and
collected in sterile tubes, which were then placed on ice before processing.
The serum GH concentrations were assessed using active ultrasensitive GH
enzyme immunoassay kits (Diagnostic Systems Laboratories, Webster, USA).
The sensitivity of the GH assay was 0.66 pg/mL; the inter- and intra-assay
coefficient of variations was less than 10%. The SPSS (V. 11) statistical package
was used for the statistical analysis of the data. ANOVA indicated that the mean
GH concentration was significantly higher in females, being 57.85 ± 2.65 uml,
than males, being 43.04 ± 3.44 uml, (F1, 77 = 11.07, p = .001, eta squared =
.13). Accordingly, the plasma GH concentrations between pulses were found
to be higher in female rats than male rats (Jansson et al., 1985).

RESULTS
GH vs. Weight and Height
Figure 1 illustrates the relations of the serum GH levels (abscissa) to the body
weight (above) and height (below) in newborn rat pups. In males (closed circles,
1750 D. D. ELALMIS AND U. TAN
Downloaded By: [TÜBTAK EKUAL] At: 07:11 13 April 2009

Figure 1. Relations of serum GH concentrations (abscissa) to body weight (A) and height (B) in
rat pups. Open circles, dashed lines: females; closed circles, straight lines, males.
GROWTH HORMONE 1751

straight lines), the serum GH concentration was not significantly related to body
weight and height (GH vs. weight: r = .00, t = 0.03, p > .95; GH vs. height:
r = .04, t = 0.25, p > .80). In females (open circles, dashed lines), the serum
GH level inversely correlated with body weight and height (GH vs. weight: r =
−.85, t = −.7.47, p < .001; GH vs. height: r = −.69, t = −4.32, p < .001).

GH vs. Right-Brain, Left-Brain, and Cerebellar Weights


Figure 2 illustrates the relations of the serum GH levels (abscissa) to the right-
brain (A), left-brain (B), right- minus left-brain (C), and cerebellar (D) weights
in the male (closed circles, straight lines) and female (open circles, dashed lines)
pups. In males, the serum GH level positively correlated with the right-brain
weight (A: closed circles, straight line, r = .76, t = 7.06, p < .001). However,
Downloaded By: [TÜBTAK EKUAL] At: 07:11 13 April 2009

Figure 2. Relations of serum GH concentrations (abscissa) to brain weight in newborn rat pups.
(A), right-brain; (B), left-brain; (C), right minus left brain; (D), cerebellum. Open circles, dashed
lines: females; closed circles, straight lines: males.
1752 D. D. ELALMIS AND U. TAN

the serum GH level was not significantly related to the left-brain weight (B:
closed circles, straight line, r = .04, t = −0.20, p > .80). The right- minus
left-brain weight significantly increased with the serum GH levels (C: closed
circles, straight line, r = .73, t = 5.99, p < .001). The cerebellar weight showed
a positive correlation with the serum GH level (r = .45, t = 3.00, p < .005).
In the female pups (dashed lines, open circles), the serum GH level was
negatively linearly correlated with the right-brain (A), left-brain (B), right-
minus left-brain (C), and cerebellar (D) weights. The correlation coefficients
were found as follows: for GH vs. right-brain, r = −.80, t = −6.19, p < .001;
for GH vs. left-brain weight, r = −.68, t = −4.23, p < .001; for GH vs. right-
minus left-brain weight, r = −.48, t = −2.47, p < .05; for GH vs. cerebellum,
r = −.84, t = −7.04, p < .001.
Downloaded By: [TÜBTAK EKUAL] At: 07:11 13 April 2009

DISCUSSION
The results suggested sexual dimorphism in relation of serum GH level to body
size. That is, the body weight and height did not show a significant relation
to the serum GH level in male litters, whereas the body weight and height
inversely correlated with the serum GH level in female litters. These results
are consistent with those previously found in human newborns. Namely, the
body weight of human newborns inversely correlated with GH concentration
from the cord blood (see Tan, 1995). This result was later replicated in another
group of human newborns, and it was found that the blood hGH concentration
from the cord blood inversely correlated with the body weight, height, and head
circumference (see Tan et al., 1998). Taken together, it may be concluded that
the blood GH is inversely related to body size, but only in prenatal females and
not in prenatal males.
This suggests, on the other hand, a sexual dimorphism in GH effects on
body size. The higher GH level in females than males suggests that the measured
GH exhibited the basal GH level in rat pups because the basal GH levels were
found to be higher in female rats than male rats (see Jansson et al., 1985).
The relation of the blood GH level to the right-, left-, and right- minus
left-brain weights also showed sexual dimorphism. Namely, the serum GH
inversely correlated with the right- and left-brain weights in females, whereas
it positively correlated with the right-brain and the right- minus left-brain
weight in males; there was no significant correlation between the serum GH
level and the left-brain weight. Interestingly, the GH’s growth promoting effect
could be revealed only for the right-brain of the male rat pups. Otherwise,
the relationships between GH and the right- and left-brain weights suggested
GROWTH HORMONE 1753

a growth limiting effect of the GH on both brain hemispheres. These results


are the first reports with regard to the sexual dimorphisms in GH effects on
body and brain size in prenatal rats. The previous studies showed a sexual
dimorphism in the control of GH secretion in mature rats (Jansson et al., 1985)
and GH levels at birth (Geary et al., 2003). The results concerning the relations
of the serum GH levels to the right- and left-brain weights in rat pups are
consistent with those on the relations of the GH concentrations from the cord
blood to the grasp-reflex strengths from the right and left hands in the newborn
babies in humans (see Tan, 1992). That is, the grasp-reflex strength from the
right and left hands of the human newborns exhibited an inverse relation to
the cord GH levels in females; there was a direct correlation between these
variables in males, similar to relations of the serum GH levels to the right- and
Downloaded By: [TÜBTAK EKUAL] At: 07:11 13 April 2009

left-brain weights in the male and female pups, in the present work.
Contrary to the GH dogma that it has no role in fetal development, based
on clinical studies with anencephalic fetuses, there is now growing evidence
indicating a prominent role of GH in fetal development from ovulation through
preimplantation to the late fetus (see Waters & Kaye, 2002). However, the
sexual dimorphism was not taken into consideration in these studies. The growth
promoting effects of GH during fetal development were reported, especially on
the skeletal growth.
For instance, Laron dwarfs (see Laron et al., 1993) and congenitally GH
deficient newborn babies (see Gluckman et al., 1992) are born shorter than
normal, whithour mentioning any sexual dimorphism in these results. Similarly,
the fetal length and weight are reduced in GH-deficient dwarf rats (Kim et al.,
1993), and in the GHR KO mice (Danilovich et al., 1999). A possible sexual
dimorphism was also not taken into consideration in these studies. Although
the experimental results of the present work are consistent with human studies
previously reported (see Tan 1992, 1995; Tan et al., 1998), there is no data to
explain the apparently indirect growth-limiting effects of GH on brain/body
development in rat pups.

REFERENCES
Ajo, R., Cacicedo, L., Navarro, C., & Sanchez-Franco, F. (2003). Growth hormone
action and differentiation of cerebral cortical cells from fetal rat. Endocrinology,
144, 1086–1097.
Chen, L., Lund, P. K., Burgess, S. B., Rudish, B. E., & McIIwain, D. J. (1997).
Growth hormone, insuline-like growth factor I, and motoneurone size. Journal
of Neurobiology, 32, 202–212.
1754 D. D. ELALMIS AND U. TAN

Danilovich, N., Wernsing, D., Coschigano, K. T., Kopchick, J. J., & Bartke, A.
(1999). Deficit in female reproductive function in GHR-KO mice; role of IGF-I.
Endocrinology, 140, 2637–2640.
Garcia-Aragon, J., Lobie, P. E., Muscat, G. E. O., Gobius, K. S., Norstedt, G., &
Waters, M. J. (1992). Prenatal expression of the GH receptor/binding protein in
the rat: A role of GH in embryonic and fetal development Development, 114, 869–
876.
Geary, M. P. P., Pringle, P. J., Rodeck, C. H., Kingdom, J. C. P., & Hindmarsh, P. C.
(2003). Sexual dimorphism in the growth hormone and insulin-like growth factor
axis at birth. The Journal of Clinical Endocrinology & Metabolism, 88, 3708–
3714.
Gluckman, P. D., Gunn, A. J., Wray, A., Cutfield, W., Chatelain, P. G., Guilbaud,
O., Ambler, G. R., Wilton, P., & Albertsson-Wikland, K. (1992). Congenital
Downloaded By: [TÜBTAK EKUAL] At: 07:11 13 April 2009

idiopathic GH deficiency is associated with prenatal and early postnatal growth


failure. Journal of Pediatrics, 121, 920–923.
Hill, D. J., Riley, S. C., Bassett, N. S., & Waters, M. J. (1992). Localisation of the
GH receptor, identified by immunohistochemistry, in second and third trimester
humanv fetal tissues and in placenta throughout gestation. Journal of Clinical
Endocrinology and Metabolism, 75, 646–650.
Hojvat, S., Emanuele, N., Baker, G., Connick, E., Kirsteins, L., & Lawrence,
A. M. (1982). Growth hormone (GH), thyroid-stimulating hormone (TSH),
and luteinizing hormone (LH)-like peptides in the rodent brain: Non-parallel
ontogenetic development with pituitary counterparts. Brain Research, 256, 427–
434.
Jansson, J. O., Eden, S., & Isaksson, O. (1985). Sexual dimorphism in the control of
growth hormone secretion. Endocrine Reviews, 6, 128–150.
Kim, J. D., Nanto-Salonen, K., Szczepankiewicz, J. R., Rosenfeld, R. G., & Glassock,
G. F. (1993). Evidence for pituitary regulation of somatic growth, IGF-I and -II,
and their binding proteins in the fetal rat. Pediatric Research, 33, 144–151.
Kolle, S., Sinowatz, F., Boie, G., Lincoln, D., Palma, G., Stojkovic, M., & Wolf,
E. (1998). Topography of GH receptor expression in the bovine embryo.
Histochemistry and Cell Biology, 109, 417–419.
Laron, Z., Lilos, P., & Klinger, B. (1993). Growth curves for Laron syndrome. Archives
of Disease in Childhood, 68, 768–770.
Noguchi, T. (1996). Effects of growth hormone on cerebral development: Morphological
studies. Hormonal Research, 45, 5–17.
Spencer, G. S. G., Robinson, G. M., Berry, C. J., & Dobbie, P. M. (1994). Alteration
of maternal growth-hormone levels during pregnancy influences both fetal and
postnatal-griwth in rats. Biology of the Neonate, 66, 112–118.
Tan, U. (1992). Human growth hormone may differentially influence the grasp reflex in
human neonates on the basis of genetically predetermined neural pattern of brain
organization in utero. International Journal of Neuroscience, 74, 87–93.
GROWTH HORMONE 1755

Tan, U. (1995). Growth hormone limits the brain/body development before birth in
relation to sex, grasp-reflex asymmetry, and familial sinistrality of human neonates.
International Journal of Neuroscience, 82, 105–111.
Tan, U., Pence, S., & Tan, M. (1998). The prenatal attenuation of brain/body
development through interactions between growth hormone, triiodothyronine,
and testosterone during prenatal development of female neonates. International
Journal of Neuroscience, 95, 237–245.
Waters, M. J., & Kaye, P. L. (2002). The role of growth hormone in fetal development.
Growth Hormone & IGF Research, 12, 137–146.
Downloaded By: [TÜBTAK EKUAL] At: 07:11 13 April 2009