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33 Genetic Background oftheRhinologic Diseases
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459
33.8.3.8 Acid Reux
It is suggested that there is a relation between
laryngopharyngeal reux and VMR based on
autonomic dysfunction [145]. Patients with
VMR and those with extraesophageal manifestations of gastroesophageal reux show ndings
of autonomic dysfunction. Patients with both
VMR and esophageal reux show a considerably greater degree of autonomic dysfunction
compared with patients with only VMR.Shaker
etal. investigated the intrapharyngeal distribution of gastric acid reuxate [159] in reux laryngitis, VMR, and control subjects using dual
pharyngeal and esophageal probes. The study
determined that the number and extent of reux
events in the esophagus and lower pharynx are
indistinguishable between patients and control
subjects.
33.9 Conclusions
Rhinologic diseases are very common worldwide. It is known that these diseases have a signicant genetic background. A lot of development
in the eld of genetics has been achieved over the
last decade, and it is expected to advance even
further in the next, as increasingly powerful analytical tools are being developed to solve the
complexities of genetic diseases. These progress
in information about the genetics of allergic diseases and new tools help not only for illuminating the molecular basis of these diseases but also
for developing new therapies. In the future, many
rhinologic diseases with chronic progress will
have a chance to be treated through new developments in the eld of genetics.
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Vomeronasal Organ
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CemalCingi, AytuğAltundağ, andİsmailKoçak
34
Core Messages
• There are still debates about the nature and
role of the vomeronasal organ in the human
nose.
• The vomeronasal organ’s remnant appears to
be a blind-ending tube lined by pseudostratied epithelium and associated with submucosal glands.
• Vomeropherin pregna-4,20-diene-3,6-dione’s
local and systemic effects help the human
VNO’s functioning and its implications for
autonomic and psychophysiological functions. Some researchers, on the other hand,
assume that the human VNO has epithelia that
may function as a chemical sensory organ, but
that there are no links between the VNO and
the central nervous system.
C. Cingi (*)
Department of Otolaryngology-Head Neck Surgery,
Osmangazi University, Eskisehir, Turkey
Medical Faculty, ENT Department, Eskisehir
Osmangazi University, Meselik Kampüsü,
Eskisehir, Turkey
e-mail: ccingi@ogu.edu.tr
A. Altundağ
Department of Otolaryngology, Istanbul Surgery
Hospital, Istanbul, Turkey
İ. Koçak
ENT Department, Liv Hospital, Istanbul, Turkey
e-mail: info@drismailkocak.com
The vomeronasal organ (VNO) is an auxiliary
olfactory system peripheral sensory organ. In
most amphibians, reptiles, and mammals, it is a
paired organ found at the base of the nasal septum or on the roof of the mouth [1].
The VNO is an accessory olfactory organ that
receives pheromones, which are chemical stimuli
that induce behavioral, reproductive, or neuroendocrine responses in individuals of the same species [2]. In the year 1703, Frederik Ruysch
discovered the vomeronasal cavities in humans.
On each side of the anterior part of the nasal septum of a young cadaver, he identied a “canalibus nasalibus.” Kölliker examined the role of the
vomeronasal cavities in the nasal septum of dead
fetuses, infants, and adults in great detail. The
cavity’s opening is evident as a pit on the septum’s surface [3].
In several mammalian species, Ludwig Lewin
Jacobson described the vomeronasal organ in great
detail. He did, however, point out that the vomeronasal structure does not evolve in humans [4].
According to a recent Bulgarian survey, VNO
is present in around 27% of the adult population
(men, 53%; women, 47%) [5].
34.1 VNO Anatomy
The researchers describe a blind-ending tube
with submucosal glands and a pseudostratied
epithelium on all sides. It appears that this struc-
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
Ö. Ö. Celebi, T. M. Önerci (eds.), Nasal Physiology and Pathophysiology of Nasal Disorders,
https://doi.org/10.1007/978-3-031-12386-3_34
465
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C. Cingi et al.
ture is the adult human vestige of the vomeronasal organ [6]. The vomeronasal cavities were
found at the base of the nasal septum’s most anterior portion, which can be seen on computed
tomography. According to histological research,
the vomeronasal cavities consisted of a pit connected to a duct running posteriorly under the
nasal mucosa. In the duct, there were several
glands that contained mucus [3]. There are some
differences in how VNO, VNO trap, and VNO
cavity are dened and identied. Researchers
have identied the variations of the nasopalatine
fossa (NPF) and the nasopalatine recess in some
studies (NPR). The endoscopic view of the vomeronasal pit poses several doubts. The NPF and
the NPR are two distinct but variable structures
found near the VNO eld. The NPF isn’t a trap
for vomit. The vomeronasal duct opening could
be hidden by a septal mucosal pit. The VNO is a
submucosal structure that lies 2–8mm above the
NPR and cannot be detected macroscopically or
endoscopically [7]. However, in another study,
endoscopy showed vomeronasal cavities in some
adults, but they lacked sensory neurons and nerve
bers [8]. The following are the main ndings of
a report on the human VNO: (1) A VNO is detectable in about two-thirds of the population, and
bilateral VNOs are present in about 40% of investigated subjects, (2) its location on the left and
right nasal septum is nearly symmetrical, and (3)
the VNO’s detectability is unrelated to age or
gender [9].
VNO has also not been reliably observed during fetal development in recent studies, and its
existence is not dependent on the gender or age of
the fetus. By weeks 6–7, the VNO is present in
human fetuses, and its ducts have opened into the
nasal cavity by the 28th week. The VNO was discovered to be made up of olfactory epithelium,
lamina propria, and a dense vascularization network when it was examined histologically. The
VNO epithelium comprises a population of cells
with neural properties that have the ability to differentiate into a chemosensory epithelium at rst,
but the neural population declines signicantly as
the fetal age increases. The ndings of these studies back up the hypothesis that the neuroepithelium present in the early stages of fetal
development is regressing [10, 11].
34.2 VNO Histology
The human VNO was discovered to have several
forms. Tall cells with discontinuous cilia on their
free surface made up the epithelium, which was
variable in thickness both medially and laterally
[12]. The anteroposterior and superoinferior
locations of human VNOs in relation to the anterior nasal spine and the nasal cavity oor were
also distinct [13].
The epithelium that lines the human VNO varies from that which lines VNOs in other animals
and from that which lines the olfactory or respiratory epithelium in humans. Many elongated cells
present a microvillar surface to the organ’s
lumen, but the majority are not like microvillar
vomeronasal sensory organs (VSNs) in other
mammals. They don’t have axons that leave the
epithelium or make synaptic interaction with
axons in the epithelium, according to research. If
these cells are chemosensitive, there is no clear
way for them to communicate with the brain [14].
Several immunomarkers have been discovered to dye these special elongated bipolar
microvillar cells [15]. The vomeronasal epithelium’s (VNE) histology tended to be highly varied.
Slender bipolar cells made up portions of stratied, respiratory, and standard pseudostratied
vomeronasal epithelia. The human VNE does not
behave like the mature olfactory epithelium,
according to mainly negative immunohistochemical ndings for OMP [16]. These cells have
physiological properties that are similar to those
found in other mammalian species’ chemosensory receptor cells. A small subset of VNE cells
had neuron- like activity, as shown by the existence of certain bipolar cells positive for both
protein gene product (PGP) 9.5 and soybean lectin. In the VNE of adult humans, immunohistochemistry was used to look for three molecular
markers: neuron- specic enolase (NSE) and PGP
9.5 for neurons and neuroendocrine cells, and
olfactory marker protein for olfactory receptor
neurons. Immunoreactive cells for NSE and PGP
9.5 have been found in the VNE [17].
Human and chimp VNOs resembled nonhomologous ciliated gland ducts found in other primates in terms of structure. The human/chimp
VNO, on the other hand, differs from the VNOs
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467
of other primates or nonhomologous epithelial
systems in the following ways: (1) bilateral epithelial tubes; (2) superiorly displaced location in
the same plane as the paraseptal cartilages; (3)
homogeneous, pseudostratied columnar morphology with ciliated regions; and (4) mucousproducing structures inside the epithelium [18].
However, the authors of a recent study discovered serial or semiserial portions of 30 fetuses
aged 7–18 weeks. Calretinin and S100 protein
staining showed the terminal nerve along the
anterior edge of the ethmoid’s perpendicular lamina, as well as the VNO along the lamina’s posterior edge. The terminal nerve was made up of 1–2
nerve bundles that passed through the cribriform
plate’s anterior end, while the VNO was made up
of 2–3 bundles behind the olfactory nerves. The
terminal nerve ran along the backside of the nasal
branch of the anterior ethmoidal nerve, crossing
it. On the lateral surfaces of the ethmoid crista
galli, multiple clusters of small ganglion cells
were discovered, which could be the sources of
both the terminal nerve and the VNO [11].
34.4 VNO Responses
There appears to be a process in or near the VNO
pit that selectively generates an electrical reaction to small amounts of certain chemicals. The
word “vomeropherin” has been proposed as a
generic term for substances that stimulate the
VNO in any species and as a name for chemicals
that evoke this response [26]. The “electrovomeronasogram” (EVG) reported from the VNO pit
region in awake human subjects is the rst form
of response. It gets its name from the electroolfactogram (EOG), which can be reported from
the olfactory epithelium’s surface in response to
odor stimulation [23]. It has also documented
preliminary evidence that bipolar cells aspirated
from the human VNO pit exhibit electrical
responses to certain “vomeropherins” as a second
form of response. These are the EVG-inducing
steroids that are linked to skin chemicals that this
group claims are human pheromones [15].
34.5 VNO Function
34.3 Genes Related toVNO
TRPC2, a mouse gene that is required for VNO
function, is a human pseudogene [19]. TRPC2 is
only expressed in the VNO, so its loss of selective
pressure can be used as a molecular marker for
when the VNO became vestigial [20]. Human
olfactory mucosa contains transcripts of the
V1RL1 vomeronasal receptor, which may indicate the fact that the accessory olfactory system
has been integrated into the primary olfactory
system in humans (and some other mammals)
[21]. A second mouse receptor subclass was discovered in the olfactory epithelium in 2006.
Some of the trace amine-associated receptors
(TAAR) in mouse urine, including one putative
mouse pheromone, are activated by volatile
amines present in the urine [22].
Humans have orthologous receptors, suggesting that there is a mechanism for detecting human
pheromones [23]. According to research, humans
have the genes for at least six of the same pheromone receptors as mice [24, 25].
Almost all social animals are known to interact
using pheromones [27]. Furthermore, studies
have shown that people can deduce a person’s sex
by smelling them [28]. In addition to the conventional olfactory system, also known as the primary olfactory system, an accessory olfactory
system has evolved in the vast majority of terrestrial animals to detect pheromones rather than
other environmental odorants [29].
Human smegma and vaginal secretions, as
well as human apocrine glands, have been found
to contain pheromones or vomeropherins [30].
Many experiments have been conducted in order
to weigh the evidence for and against human
VNO function, to distinguish this problem from
the question of pheromone signaling, and to provide a working denition of “pheromone.”
Humans have VNO, which is considered to be
nonfunctional since the vomeronasal receptor
and signal transduction genes in humans are
pseudogenes [31]. In addition to a functional
vomeronasal-pituitary pathway and an effect on
gonadotropin pulsatility in adult humans, the
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C. Cingi et al.
vomeropherin also has autonomic reex effects
after VNO stimulation [32].
Cranial nerve 0 and VNO bers are embryologically independent of the olfactory nerve,
according to studies in adult brains and fetuses
[10, 11]. The ubiquitous hypothalamic-pituitarygonadal axis is thought to play a role in the
unconscious perception of particular odors that
inuence the autonomic and reproductive hormonal systems [33, 34]. Furthermore, research
indicates that it may play a role in detecting pheromones for mate selection and neuromodulation
of reproductive functions. VNO has been blamed
for intra-specic chemical communication by
pheromones, which are chemical messengers
secreted externally by one animal and detected
by another [35, 36].
In the male human VNO, vomeropherin
pregna-4,20-diene-3,6-dione (PDD) has a dosedependent local effect. Then comes a mild parasympathomimetic effect, which involves a 10%
rise in vagal tone and a decrease in the frequency
of electrodermal activity events. Furthermore,
local delivery of PDD to the male human VNO
reduces serum LH and testosterone levels. This
research backs up the human VNO’s mechanism
and the effects it has on autonomic and psychophysiological processes, as well as neuroendocrine secretions [37]. Occlusion or absence of the
VNO did not affect the perceptual measurements
or functional processing of the putative human
pheromone androstadienone, according to
another study. [38].
As a result, the human VNO has epithelia that
could potentially act as a chemical sensory organ;
however, the VNO receptor genes in humans are
nonfunctional pseudogenes. Furthermore, although
the human VNO includes sensory neurons, there
seem to be no interactions between the VNO and
the central nervous system [39].
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