Download Asymmetry of the Neuroendocrine System

Asymmetry of the Neuroendocrine System
Ida Gerendai and Béla Halász
There is information on the lateralization of hypothalamic, limbic, and other brain structures involved
in the control of the endocrine glands. Sided differences between paired glands, including their
peripheral innervation, and relevant clinical observations on asymmetry are also known. Data
suggest predominance of the right half of brain structures in controlling gonadal function.
T
he discovery of asymmetry and cerebral dominance dates
back to 1861, when Paul Broca reported that the lesions
in his aphasic patients lay on a delimited region of the left
hemisphere. On the basis of this fundamental and subsequent observations, a classic theory of asymmetry was formulated comprising the existence of a single dominant (left)
hemisphere and the presence of asymmetry exclusively in
humans, in the cerebral cortex. The theory of asymmetry discouraged scientists for a long time from research aimed at
extending asymmetry to brain regions other than the cerebral
cortex and/or to other species. Since the late 1960s, it has
become evident that each hemisphere is superior in certain
functions and that asymmetry is present throughout the animal kingdom. Furthermore, a wealth of data indicates asymmetry in subcortical areas and in nonneuronal structures.
Morphological, biochemical, and pharmacological asymmetries have been revealed underlying biological mechanisms
of functional asymmetry. Recent findings even indicate that
asymmetry also exists in nonliving structures down to the
level of elementary particles.
The discovery of asymmetry in the neuroendocrine system
was quite accidental. Studies leading to the first description
of asymmetry in neural control of the endocrine glands were
originally designed to demonstrate the existence of a direct
neural pathway between the brain and the peripheral
endocrine glands. To provide experimental observations supporting this view, a special experimental protocol was
designed: brain lesion, right or left, was performed in animals
subjected to removal of the right or the left endocrine gland,
or changes in biochemical parameters were measured in the
right and left halves of the hypothalamus following right- or
left-sided extirpation of the ovary. Unexpectedly, the results
of the experiment, in which the gonadotropic hormonereleasing hormone (GnRH) content of the hypothalamus
halves, studied in hemiovariectomized rats, indicated that in
intact control animals the GnRH content is significantly
higher in the right half of the hypothalamus than in the left
half (7). This observation was followed by other findings indicating the existence of different kinds of asymmetries at each
level of the neuroendocrine system. In this review, we summarize these data obtained in animals and also include rele-
I. Gerendai and B. Halász are at the Neuroendocrine Research Laboratory,
Hungarian Academy of Sciences and Semmelweis University, Department of
Human Morphology and Developmental Biology, Budapest, H-1094, Hungary.
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vant clinical observations. Hypothalamic asymmetry is
discussed first, followed by asymmetry of temporolimbic and
cerebral cortical structures. The next section describes asymmetry at the level of peripheral innervation of paired
endocrine glands. Finally, the data that indicated asymmetry
at the level of paired endocrine glands are discussed.
Hypothalamic asymmetry
As mentioned above, the first observation concerning the
asymmetry in the neuroendocrine system was the significant
difference in the GnRH content between the right and left
halves of the hypothalamus of intact female rats. Further studies indicated that in the male rat the right side of the hypothalamus also contains significantly more GnRH than the left
(1). In male mice, the number of GnRH neurons has been
reported to be more numerous on the right side of the brain
(9). In humans, a higher concentration of thyrotropin-releasing
hormone was found in the left hypothalamic ventromedial,
dorsomedial, and paraventricular nuclei (3).
Besides the biochemical differences between the right and
left sides of the hypothalamus, some data indicate functional
asymmetry within the hypothalamus. In the male rat, unilateral deafferentation of the hypothalamus prevents the hemicastration-induced follicle-stimulating hormone (FSH) rise
only when right hypothalamus intervention is combined with
right orchidectomy. In female rats, right- but not left-sided
lesion of the anterior hypothalamus or the retrochiasmatic
area interferes with the hemiovariectomy-induced compensatory ovarian hypertrophy and the rise in serum FSH concentration that follows hemiovariectomy. Lesion or atropine
implantation on the right side of the anterior hypothalamus
on the day of estrus severely affects ovulation. Development
of female sexual behavior can be differentially disturbed by
early implantation of estradiol in the right or the left half of
the hypothalamus. Implantation of the steroid hormone in the
right side of the hypothalamus leads to masculinization (e.g.,
preference for other females), whereas a similar intervention
on the left side induces defeminization (e.g., loss of estrous
cycle) (for details and references see Ref. 6).
These findings clearly indicate that gonadal and, in more
generalized terms, reproductive functions are governed by
the hypothalamus, which exhibits both biochemical and
functional asymmetry. On the basis of the data available, it
seems that the right side of the hypothalamus plays a dominant role in the control of reproductive functions.
0886-1714/99 5.00 © 2001 Int. Union Physiol. Sci./Am.Physiol. Soc.
Concerning the functional asymmetry of neural pathways
to and from the hypothalamus involved in the control of the
mitotic activity of the thyroid follicular cells, it has been
reported that posterior deafferentation on the left side of the
hypothalamus induces a decrease in the mitotic index of the
follicular cells of both lobes of the gland. In hemithyroidectomized rats, a similar knife cut on the same side prevents the
hemithyroidectomy-induced increase in the proliferative
activity of the remaining lobe (10).
Asymmetry in temporolimbic and cerebral cortical
structures
In adult males, left-sided deafferentation in the temporal
lobe combined with left orchidectomy results in a decrease in
steroidogenesis of the remaining testis with no change in
serum luteinizing hormone (LH) concentration. Other combinations are ineffective in this respect. A similar effect was
observed in prepubertal animals. However, in this case the
right-sided brain surgery plus left hemicastration combination
was effective. In contrast in hemiovariectomized adult females,
right- but not left-sided deafferentation in the temporal lobe
interfered with the development of compensatory ovarian
hypertrophy, regardless the side of hemicastration (5). These
observations indicate the functional asymmetry of the amygdala in the control of gonadal functions. Furthermore, the data
also suggest that the dominance is sex and age dependent.
There are also clinical data suggesting the asymmetry of the
temporal lobe in the control of reproductive functions. Among
women with partial seizures of temporal lobe origin, reproductive disorders are unusually common. Furthermore, polycystic ovarian syndrome is predominantly associated with
left-sided epileptiform discharges, whereas hypothalamic
amenorrhea is related predominantly to right-sided discharges
(8). A possible relationship between handedness and female
reproductive functions is suggested by the earlier appearance
of both menarche and menopause in left-handed women (12).
Recent data indicate that there is a functional asymmetry in
the medial prefrontal cortex concerning neuroendocrine and
autonomic stress responses of the rat. Both prestress and acute
restraint stress-induced plasma corticosterone levels are lower
in animals with right or bilateral lesion of the medial prefrontal cortex but not with left-sided surgery. In addition, stress
ulcer development is greatly reduced after right or bilateral
cortical lesion (13). Furthermore, greater binding capacity of
mineralocorticoid receptors has been demonstrated in the
right than in the left hippocampus (11). Autopsy data indicate
that in suicides the left, but not the right, adrenal gland is
heavier than in control, sudden death cases (14).
Asymmetry at the level of the peripheral innervation of
paired endocrine glands
Few data are available on the asymmetry of nerves to and
from the paired endocrine glands. At this level of regulation,
the asymmetry mainly concerns the functional laterality of
the vagus nerve of the gonads. In adult male rats, right-sided
vagotomy results in a significant rise in serum LH concentra-
tion, whereas vagotomy on the left side does not significantly
alter serum LH level. In prepubertal hemicastrated animals,
right-sided vagotomy and right-sided hemicastration induces
a significant decrease in serum LH and FSH concentrations
and in steroid secretion of the remaining testis. Also, in
female rats, the effect of unilateral vagotomy depends on the
side of vagotomy, on the side of hemiovariectomy (side of the
remaining ovary), and on the age of the animal at the time of
surgery. Interestingly enough, in male but not in female mice
the left hypogastric ganglion is significantly larger that the
right one (for details and references see Ref. 6).
Asymmetry at the level of paired endocrine glands
It is well known that the venous drainage of the left and
right gonads and of the left and right adrenal glands is different. The right veins of these organs open into the inferior vena
cava, whereas the left veins empty into the left renal vein. In
humans, the right testis is heavier than the left, and the left
one has a lower position in the scrotum. There are no sided
differences between the weight and localization of the
ovaries in most species. In birds, however, only the left ovary
is functional, the right is rudimentary. Both in humans and
rats the left adrenal gland weighs more than the right. The
right lobe of the thyroid gland is usually larger and more vascularized than the left lobe.
There are reports indicating functional asymmetry of the
testes. The right testis exhibits a greater response either to LH
treatment or to hemicastration than the left gonad (4). Besides
its lower functional capacity, the left testis is more vulnerable
than the right one, and in humans, there is a greater frequency
of cryptorchidism and varicocele on the left side. Clinical data
indicate that in humans adrenal carcinomas causing Cushing’s
“…clinical data suggesting the asymmetry of the
temporal lobe in the control of reproductive functions.”
syndrome occur more frequently on the right side, whereas
adrenal tumors inducing primary aldosteronism are more frequent on the left side. Thyroid diseases, such as solitary nodules or disorders causing diffuse increase in size of the gland,
affect mostly the right lobe of the thyroid gland (for references,
see Ref. 6).
Conclusion
The data reviewed here clearly indicate that asymmetry does
exist in the neuroendocrine system and that it is present at each
organizational level. Most of the findings available are related
to the gonads and their regulatory structures. It seems that in
the control of endocrine reproductive functions right-sided
neuronal structures play a predominant role (this trend is most
evident in the hypothalamus). Experimental data suggest that
this dominance is sex and age related. During ontogeny, asymmetry shifts from one side to the other, and the characteristic
pattern gets fixed only after puberty. On the basis of recent
reports, it appears to be well established that the right
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FIGURE 1. A very simplified scheme of the neural and humoral connections between the different levels of the two sides of the neuroendocrine system. L, left
side; R, right side; 1, neurons producing hypophysiotropic neurohormones; 2, hypophysiotropic neurohormones; 3, pituitary tropic hormones; 4, target endocrine
gland hormones. Broken lines indicate humoral connections.
hemisphere also plays a dominant role in the control of the
hypothalamic-pituitary-adrenal axis. These results are consistent with the view that the right hemisphere has a special role
in the control of autonomic functions essential for survival.
Concerning the control of thyroid functions, the few data available suggest a left-sided dominance. Systematic experimental
work is required to study asymmetry of neural structures controlling the secretion of anterior pituitary hormones with no
peripheral endocrine glands (prolactin, growth hormone).
Several important questions arise, such as how the asymmetry of the neuroendocrine system is operating, what is the
mechanism of the lateralized effects, and what is the biological significance of asymmetry? None of these questions can
be answered satisfactorily at this time. In spite of this, we
think these issues should be very briefly discussed.
Depending on whether the asymmetry resides in the central nervous system or in the peripheral endocrine glands (or
in both), in essence two basic mechanisms and their combination can be assumed (Fig. 1). The influence generated in
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the asymmetrical cerebral structures can affect the peripheral
endocrine glands through the pituitary and via direct neural
pathways between the central nervous system and the target
endocrine gland. The effect of the peripheral endocrine
glands can be realized by hormonal feedback and/or by pure
neural pathways. On the basis of available data, it may be
assumed that the full control of the target endocrine glands
requires asymmetry of certain regulatory nervous structures,
but the pattern of cerebral asymmetry can be modified by the
peripheral endocrine glands. If one takes into account that
asymmetry is a trait of nature, it may be assumed that the
neuroendocrine asymmetry is just one example of this trait.
The biological mechanisms leading to cerebral lateralization and left-right asymmetry in handedness include developmental, hormonal, and genetic aspects (2). Nothing is
known, however, about the developmental mechanisms in
neuroendocrine asymmetries.
We thank Dr. Katalin Kocsis for her help in preparing this review.
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Excitatory Synaptic Transmission in Neonatal Dorsal
Horn: NMDA and ATP Receptors
Rita Bardoni
Postnatal development sees a strong synaptogenesis in rat superficial dorsal horn. My studies show
that synapses mediated by two excitatory neurotransmitters, glutamate and ATP, are functional
since the very first postnatal days. Using an electrophysiological approach, the functional
properties of two receptors activated by these neurotransmitters, glutamatergic NMDA and
ATP ionotropic receptors, are described.
T
he superficial dorsal horn is the spinal cord area involved
in the elaboration of nociceptive stimuli. It is divided into
lamina I and lamina II and, at complete maturation, receives
the sensory input through the myelinated Aδ fibers and the
small-diameter, unmyelinated C fibers. The nociceptive signal
is elaborated by the local circuits of excitatory and inhibitory
interneurons, which are particularly abundant in lamina II, is
modulated by the descending fibers, and is finally transmitted
to the higher centers by the projecting neurons, mainly located
in laminae I, V, and VI.
Excitatory neurotransmitters in spinal cord dorsal horn
In the last 10 years, several electrophysiological studies
have described the principal neurotransmitters and receptors
that mediate synaptic transmission in superficial dorsal horn,
and particularly in lamina II (Substantia gelatinosa). By electrically stimulating the primary afferent fibers contained in the
R. Bardoni is in the Dipartimento di Scienze Biomediche-Sezione di Fisiologia, Università di Modena e Reggio Emilia, 41100 Modena, Italy.
0886-1714/99 5.00 © 2001 Int. Union Physiol. Sci./Am.Physiol. Soc.
dorsal root, excitatory postsynaptic responses were evoked
and recorded from lamina II neurons. These studies, obtained
in adult rats, showed that the principal excitatory neurotransmitter released by both Aδ and C fibers is glutamate, acting on
receptors of non-N-methyl-D-aspartate (NMDA) and NMDA
types (19). At membrane potentials close to the neuron resting
potential, postsynaptic responses seemed to be predominantly
mediated by non-NMDA receptors. Focal stimulation of the
ventral region of lamina II, which preferentially activates the
interneurons, evoked excitatory postsynaptic potentials,
which are also mediated by glutamate and predominantly sustained by non-NMDA receptors (20).
Although these studies have indicated that glutamate is the
most common fast excitatory neurotransmitter in superficial
dorsal horn of adult animals, several authors have proposed,
during the last 40 years, that ATP can also act as an excitatory
neurotransmitter in this region. Experiments carried out on
dorsal horn cultured neurons have proven that the application
of ATP can excite a subpopulation of neurons (9). Despite this
evidence, the role of ATP as a neurotransmitter has not been
directly demonstrated and a modulatory action of ATP on glutamatergic postsynaptic responses has been suggested (12).
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