COMPARISON OF FGF -8, FGF -10, FGF- RECEPTOR 2,
ANDROGEN RECEPTOR, ESTROGEN RECEPTOR-Α
AND SS IN HEALTHY AND HYPOSPADIAC CHILDREN
Emaratpardaz N, Turkyilmaz Z, Karabulut R, Dayanir D, Kaya C, Sert AAE, Arkan G, Ucaner FA, Kapisiz A, Eryilmaz S, Atan A, Sonmez K
*Corresponding Author: Prof. Ramazan Karabulut, MD, Gazi University Faculty of Medicine,
Department of Pediatric Surgery, Besevler, 06550, Ankara-Turkey. Tel: +90 312 2026210;
Fax: +90 312 2230528. E-mail: karabulutr@yahoo.com, ramazank@gazi.edu.tr
page: 21
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DISCUSSION
Hypospadias is considered the most common con-
genital anomaly after undescended testis in males. It is
thought that there are multifactorial causes in the etiology
of hypospadias, and there are many studies in the litera-
ture on molecular, genetic and environmental factors for
etiology [1,2,13,14]. Hypospadias can arise as a result of
embryological defects that affect the development of the
urethra, which is connected to mesothelial-epithelial in-
teraction, as well as the preputium and penile skin, which
are of ectodermal origin [7]. It has been demonstrated that
androgens enable the development and differentiation of
the mouse and human penis, and that hypospadias results
from a lack of androgens. Pregnant women who receive
diethylstilbestrol (DES), a synthetic estrogen, have an
increased risk of developing hypospadias [15]. Preopera-
tive androgen stimulation has demonstrated to enhance
penile size but not the risk of postoperative problems, and
the degree of hypospadias does not alter the lengthening
of the penis in response to androgen stimulation [16]. AR
mutations have also been found to be associated with hy-
pospadias [17]. Low serum testosterone levels, decrease
in androgen-dependent pathways in the cell nucleus and
increase in cytoplasmic estrogen-dependent pathways may
cause hypospadias and undescended testis [14]. Intrauter-
ine factors, such as abnormal androgen production by the fetal testes, partial androgen insensitivity in the target
tissues of the developing genitalia, and early atrophy of
Leydig cells and premature cessation of androgen stimu-
lation, have been implicated. In hypospadias, especially
in its severe forms, abnormalities have been reported in
the enzyme 5-alpha-reductase type 2, which catalyzes the
conversion of testosterone to dihydrotestosterone [10].
For both the male and female sexes, it is well established
that ERs and estrogen are essential for healthy genital
development. The estrogen derivative diethylstilbestrol
and the anti-estrogen letrozole (an aromatase inhibitor)
have been administered to people and animals, and stud-
ies have shown that hypospadias develop as a result of an
imbalance in estrogen levels [15].
Contrary to what Khanna et al.’s investigation found
in the foreskin of children with and without hypospadias
circumcision samples showed enhanced ER expression and
decreased AR expression [10]. According to our research,
children with hypospadias have more ER and AR recep-
tors in their foreskins. Again, in the preliminary study of
Pichler et al. on this subject, it was shown that AR mRNA
expression and IHC AR protein level and AR protein stain-
ing in nuclear staining increased in the foreskin of children
with hypospadias, and this increase was correlated with the
degree of hypospadias. They stated that the elevation of
AR mRNA and AR protein in preputium samples of boys
with hypospadias is an indirect indicator of decreased AR
DNA binding capacity. Therefore, they pointed to a signal
defect indicating more deficient polypeptide encoding as
a possible cause of hypospadias. They stated that more
research on the notion should be conducted using struc-
tural analysis of AR to ascertain whether the degree of AR
signaling malfunction and the severity of hypospadias are
indicated by differences in the expression of AR mRNA
and AR protein [8]. Although expression studies were not
performed in our study, AR levels were found to be high in
the tissue, and results supporting this theory were obtained.
In the study of Celayir et al., in which the skin obtained
from 33 children with hypospadias was examined, ER was
found to be positive in 29 (87.8%) tissues and AR in 12
(36.4%) tissues. The progesterone receptor was found to
be negative (0%) in all specimens [18].
According to Cunha et al., estrogens are essential for
the development of the penile and clitoral regions in hy-
enas, as well as for determining the location of the urethral
orifice, providing flexibility to the urethral meatus, and
facilitating epithelial fusion events that are required for the
correct formation of the distal urethra, urogenital sinus,
and foreskin. Significant tissue expression of androgen
and estrogen receptors is linked to the effects of prenatal
androgens, anti-androgens, and decreased production of
estrogen, indicating that estrogen, like androgen, plays an
active role in prenatal penile development [19]. Celayir
et al. described the predominant expression of ERs in the
penile tissue of children with hypospadias as a postnatal
reflection of impaired ER and AR interaction during the
intrauterine development of external genitalia and inter-
preted that impaired AR and ER interaction may play a role
in the development of hypospadias and external genital
organs [18]. Similarly, Qiao et al. investigated the effects
of estrogen in hypospadias and circumcision tissue. They
found the mRNA expression of ER-α and β (dominant
character in foreskin without hypospadias) significantly
lower in hypospadiac skin compared to the control group
[9]. In addition, ER-β was IHC stained weakly in preputial
tissue, but prominently in skin without hypospadias. ER-α,
on the other hand, was weakly stained in without hypospa-
dias and mildly hypospadiac skin but could not be detected
in severe hypospadias [9,10]. As a result, they stated that
there is a tendency towards lower ER expression levels
in severe hypospadias compared to mild hypospadias,
and changes in ER levels play a role in the development
of normal and abnormal foreskin [9]. In our study, both
ER and AR were found to be increased in hypospadiac
skin. These results are evidence that both estrogen and
androgens play a role in the development of the genital
system and the formation of hypospadias. The increased
ER and AR receptor scoring in patients with hypospadias
can be shown as the continuation of the above-mentioned
and beginning of the intrauterine ER and AR balance, and
perhaps the body’s attempt to balance this imbalance.
The union of the urethral folds and the formation of
the genital tubercle depend on FGFs, especially FGF-8,
FGF-10, and FGFR-2. The development of severe hypo-
spadias in mutant mice has also been demonstrated. Since
members of the FGF family have a role in the interaction
between mesenchyme and urothelium, the development of
genital tissues, it has been demonstrated that abnormalities
increase the risk of hypospadias [20]. Single-base muta-
tions in FGF-8, FGF-10, and FGFR-2 are associated with
hypospadias in humans, and it has been shown to increase
the risk (3-4 times) of hypospadias compared to the con-
trol group [7]. However, studies on the concentration or
receptor density of these factors in the foreskin or penile
tissue are limited. In the pioneering study of Haid et al.
investigating the density of FGF family components in
the hypospadias foreskin, no difference was found in the
expression levels of FGF-8, FGF-10, FGFR-2 mRNA in
the foreskin of 32 hypospadias patients compared to the
normal foreskin, but a significant difference was observed
in the IHC staining distribution [7]. Compared to the con-
trol group, IHC staining of these markers were found to be
higher (2/3) in a higher pattern, especially in those with
hypospadias in the epidermis, while these markers were more pronounced in those with proximal hypospadias than
in those with distal hypospadias (p<0.05). While these
HGFs were stained in a higher pattern in the dermis than
in the control group (B/C), they showed a similar stain-
ing pattern among hypospadias types. Haid et al. empha-
sized that they showed that FGFs play an active role in
the formation of hypospadias by associating their results
with hypospadias caused by mutations of FGF-8, FGF-
10 and FGFR-2 in mouse models. These findings offer
compelling evidence in favor of the theory that mutations
in FGF components associated with the initial phases of
genital development could impact tissues produced from
human ectodermal tissue. This implies that people with
hypospadias may have significantly changed dartos fascia
microanatomy as a result of FGFs acting on mesenchymal
tissues. The induction of overlaying epithelial differentia-
tion by mesenchymal FGF production is a well-established
phenomenon. Cross-epithelial-mesenchymal boundaries
have been shown to exhibit both directionally and recipro-
cally active FGF signaling. They did not make any specific
comments about the development of hypospadias, saying
that poor wound healing and the frequency of complica-
tions are mostly reflected in the changes in this FGF family
in patients with severe hypospadias [7]. In our study, which
is the second study on this subject, no mRNA expression
study was performed, but lower scores were obtained in the
hypospadias group in the IHC studies of FGF-8, FGF-10,
and FGFR-2 in both epidermis and dermis.
Expression of FGF-8 and FGF-10, especially FGFR-
2, is positively regulated by AR receptors based on andro-
gen response element sequences in human hypospadias
foreskin tissue. However, AR expression works indepen-
dently of FGFs and without feedback [21, 22]. The changes
in these FGF values in our study and Haid’s study may
be due to the disruption of the balance between FGFs and
AR, which was described above [7]. Despite the low FGF
in our study, the low AR levels may be due to the lack of
feedback.
While endodermal FGFR-2 deletion causes mild hy-
pospadias and defective urethral epithelium, ectodermal
FGFR-2 deletion causes severe hypospadias and ventral
prepuce loss [23]. FGF-8, FGF-10, and FGFR-2 are closely
linked through Sonic Hedgehog regulation, particularly
with the formation of the limbs and genital tubercle at an
early androgen-independent stage of embryonic develop-
ment. Mesenchymal FGF signaling affects the ectodermal
and endodermal epithelium, causing overgrowth of the
genital tubercle. Although it has been shown in the litera-
ture in mouse models that FGF-8, FGF-10 and FGFR-2
affect the development of tissues of ectodermal origin,
such as penile skin and foreskin, this finding has not yet
been confirmed in human tissue [23]. Whether it is the
study of Haid et al. or our own study, although there are
different results due to the limitations of the studies on
this subject, penile tissue FGF-8, FGF-10 and FGFR-2
uptake and scores were different compared to the control
group in these studies, and the FGF family also had genital
development in humans, and evidence that it is associated
with hypospadias [7].
The limitations of this study are the limited number
of cases due budget limitations, the inability to measure
blood estrogen and androgen levels, and the inability to
express mRNA. As in other hypospadias studies, the results
reflect a small group because they sample a single ethnic
population or race. The strength of this study is that AR,
ER, and FGF-8, FGF-10, and FGFR-2 are the only studies
that looked at the same time.
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