Associations among hypospadias, cryptorchidism, anogenital distance, and endocrine disruption.
ABSTRACT Endocrine disruptors, such as environmental compounds with endocrine-altering properties, may cause hypospadias and cryptorchidism in several species, including humans. Anogenital distance is sexually dimorphic in many mammals, with males having longer anogenital distance on average than females. Animal models of proposed endocrine disruptors have associated prenatal exposure with hypospadias, cryptorchidism, and reduced anogenital distance. Human studies have correlated shorter anogenital distance to in utero exposure to putative endocrine disruptors. We review preliminary data suggesting that anogenital distance is reduced in boys with hypospadia and cryptorchidism. Hence, human hypospadias and cryptorchidism may be associated with reduced anogenital distance as a result of endocrine disruption.
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ABSTRACT: Di-(2-ethylhexyl) phthalate (DEHP) is the most widely used plastizer in the world and can suppress testosterone production via activation of oxidative stress. Genistein (GEN) is one of the isoflavones ingredients exhibiting weak estrogenic and potentially antioxidative effects. However, study on reproductive effects following prepubertal multiple endocrine disrupters exposure has been lacking. In this study, DEHP and GEN were administrated to prepubertal male Sprague-Dawley rats by gavage from postnatal day 22 (PND22) to PND35 with vehicle control, GEN at 50 mg/kg body weight (bw)/day (G), DEHP at 50, 150, 450 mg/kg bw/day (D50, D150, D450) and their mixture (G + D50, G + D150, G + D450). On PND90, general morphometry (body weight, AGD, organ weight, and organ coefficient), testicular redox state, and testicular histology were studied. Our results indicated that DEHP could significantly decrease sex organs weight, organ coefficient, and testicular antioxidative ability, which largely depended on the dose of DEHP. However, coadministration of GEN could partially alleviate DEHP-induced reproductive injuries via enhancement of testicular antioxidative enzymes activities, which indicates that GEN has protective effects on DEHP-induced male reproductive system damage after prepubertal exposure and GEN may have promising future in its curative antioxidative role for reproductive disorders caused by other environmental endocrine disruptors.BioMed Research International 01/2014; 2014:598630. · 2.71 Impact Factor
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ABSTRACT: The purpose of this study was to assess the relationship between anogenital distance (AGD) measures and semen quality and serum reproductive hormone levels in Caucasian young men from southern Spain. Two variants of AGD [from the anus to the posterior base of the scrotum (AGDAS ) and to the cephalad insertion of the penis (AGDAP )] were assessed in 215 university students. Semen parameters (semen volume, sperm concentration, total sperm counts, motility and morphology) and serum reproductive hormones (follicle stimulating hormone, luteinising hormone, inhibin B, testosterone, calculated free testosterone, oestradiol and sex hormone-binding globulin) were also determined. Associations between AGD measures and the semen quality and reproductive hormone levels were tested using multiple regression analyses. Overall, median sperm concentration was 44.0 × 10(6) ml(-1) (5th-95th percentiles: 8.9-129 × 10(6 ) ml(-1) ), median total sperm count was 121 × 10(6) (18.0-400 × 10(6) ), and mean (SD) testosterone level was 21.7 nmol/l (6.9). Mean (SD) AGDAS and AGDAP measures were 48.3 mm (11.6) and 128 mm (12.0) respectively. In the multivariable analysis, AGD measures were not associated with any semen parameters or any of the reproductive hormone levels, which is in contrast to results of studies of US young men or infertile men. Further research is warranted to confirm these findings. © 2015 Blackwell Verlag GmbH.Andrologia. 02/2015;
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ABSTRACT: Androgen action during the fetal masculinization-programming window (MPW) determines the maximum potential for growth of androgen-dependent organs (e.g. seminal vesicles, prostate, penis, perineum) and is reflected in anogenital distance (AGD). As such, determining AGD in postnatal life has potential as a lifelong easily accessible biomarker of overall androgen action during the MPW. However, whether the perineum remains androgen-responsive in adulthood and thus responds plastically to perturbed androgen drive remains unexplored. To determine this, we treated adult male rats with either the anti-androgen Flutamide, or the estrogen Diethylstilbestrol (DES) for five weeks, followed by a four-week wash-out period of no treatment. We determined AGD, and its correlate anogenital index (AGI; AGD relative to bodyweight), at weekly intervals across this period and compared this to normal adult rats (male and female), castrated male rats, and appropriate vehicle controls. These data showed that, in addition to reducing circulating testosterone and seminal vesicle weight, castration significantly reduced AGD (by ∼17), demonstrating that there is a degree of plasticity in AGD in adulthood. Flutamide treatment increased circulating testosterone yet also reduced seminal vesicle weight due to local antagonism of androgen receptor. Despite this suppression, surprisingly, Flutamide treatment had no effect on AGD at any time-point. In contrast, whilst DES treatment suppressed circulating testosterone and reduced seminal vesicle weight, it also induced a significant reduction in AGD (by ∼11%), which returned to normal one week after cessation of DES treatment. We conclude that AGD in adult rats exhibits a degree of plasticity, which may be mediated by modulating local androgen/estrogen action. The implications of these findings regarding the use of AGD as a life-long clinical biomarker of fetal androgen action are discussed.Endocrinology 11/2014; · 4.72 Impact Factor
Associations Among Hypospadias,
Cryptorchidism, Anogenital Distance, and
Michael H. Hsieh, MD, PhD, Benjamin N. Breyer, MD, Michael L. Eisenberg, MD,
and Laurence S. Baskin, MD
Michael H. Hsieh, MD, PhD
Scott Department of Urology, Texas Children’s Hospital, Clinical
Care Center, Baylor College of Medicine, Suite 660, 6621 Fannin
Street, Houston, TX 77030, USA.
Current Urology Reports 2008, 9:xx–xx
Current Medicine Group LLC ISSN 1527-2737
Copyright © 2008 by Current Medicine Group LLC
Endocrine disruptors, such as environmental
compounds with endocrine-altering properties, may
cause hypospadias and cryptorchidism in several
species, including humans. Anogenital distance is
sexually dimorphic in many mammals, with males
having longer anogenital distance on average than
females. Animal models of proposed endocrine
disruptors have associated prenatal exposure with
hypospadias, cryptorchidism, and reduced AGD.
Human studies have correlated shorter anogenital
distance to in utero exposure to putative endocrine
disruptors. We review preliminary data suggesting
that anogenital distance is reduced in boys with
hypospadia and cryptorchidism. Hence, human
hypospadias and cryptorchidism may be associated
with reduced anogenital distance as a result of
Hypospadias occurs in approximately 1 in 125 live male births
. Cryptorchidism occurs in 3% of full-term and 30% of
preterm boys. Although genetic syndromes are an appealing
explanation for these genital anomalies, at best they account for
a small fraction of cases . An alternative hypothesis is that
genetics determine susceptibility
hypospadias and cryptorchidism, and environmental factors
provide the final impetus leading to expression of these
Anogenital distance, a sexually dimorphic measure of
perineal length, may be modulated by hormonal factors, and has
been noted to be shortened in male animals exposed to
endocrine disorders in utero. Furthermore, recent studies have
suggested that anogenital distance is reduced in male infants
who exhibit higher levels of phthalates, a group of putative
endocrine disorder compounds [3••]. This study reported an
association between phthalate levels and cryptorchidism, but
otherwise no human studies have linked shortened anogenital
distance with genital defects such as hypospadias and
This review examines a possible triad of association
among endocrine disruptors, hypospadias, cryptorchidism, and
reduced anogenital distance.
to development of
Anogenital distance results from the development of the genital
tubercle, genital swellings, and cloacal membrane into the penis
or clitoris, scrotum or labia majora, and anus, respectively. In
multiple mammalian species, including rodents, cows, whales,
monkeys, and humans, males have a longer anogenital distance
than females, suggesting that this metric is under hormonal
influence (Table 1) [4•].
Further evidence for endocrine modulation of anogenital
distance exists in the finding that female mice that develop in
utero adjacent to two male fetuses feature longer anogenital
distance than do females next to no male fetuses . Alterations
in human anogenital distance thought to be due to endocrine
abnormalities were first noted in girls with congenital adrenal
hyperplasia, who have longer anogenital distance than girls
without the disorder .
Anogenital distance has been identified as an end point in
reproductive toxicity studies, but disagreement persists over the
ideal instruments for measurement and which forms of perineal
length measurement best represent anogenital distance and
associated endocrine disruption, if any. For example, past work
has used calipers placed on the patient [3••,4•,7••]; a suture
placed on the patient and then measured on calipers
(unpublished observations); or surgical rulers placed on the
patient for measurement, as in the present study. It is apparent
that significant measurement discrepancies may arise from use
of calipers, which do not follow the contour of the scrotum,
versus suture or flexible surgical rulers which can conform to
the soft tissue of the perineum. Further work is required to
establish the optimal methods of measuring anogenital distance.
Previous human studies have featured a variety of
measurements when referring to anogenital distance: the
distance from the anus to the most posterior, midline point of
the scrotum [4•]; the distance from the anus to the most inferior,
midline point of the penoscrotal junction; and the distance from
the anus to the most superior, midline point of the penopubic
junction [3••]. We propose for the sake of clarity that until a
consensus arises regarding the best perineal length for
measurement, these metrics should be referred to as posterior
anoscrotal distance (PASD), anterior anoscrotal distance
(AASD), and anogenital distance, respectively (Fig. 1). This
review uses this nomenclature, but also refer to anogenital
distance and perineal lengths as umbrella terms for all three
perineal measurements. Regardless of terminology, the
biological significance and reproducibility of these various
perineal measurements remains to be determined.
US Agency guidelines for
Possible Associations Among Anogenital
Distance, Endocrine Disruption, and Genital
Anomalies in Animal Models
The testicular dysgenesis
cryptorchidism, hypospadias, male infertility, and testicular
cancer are on the rise because of environmental factors
affecting male reproductive health . Suspected causes include
compounds that may disturb normal endocrine development in
Over 200 studies spanning multiple species have
evaluated the role of endocrine disruptors. Animal studies of
putative endocrine disorders have demonstrated increased rates
of genital defects and decreased anogenital distance in males
with prenatal exposures. For example, male rats exposed in
utero to di(n-butyl) phthalate have been shown to develop
reduced anogenital distance and abnormalities of the penis
(hypospadias), seminal vesicles, prostate, epididymes, and
testes . Male offspring of rats administered the fungicide
vinclozolin during pregnancy have infertility, shortened
anogenital distance, and reduced prostate weights .
Similarly, male rats exposed to 2,3,7,8-tetrachlorodibenzo-p-
dioxin in utero demonstrate delays in testicular descent and
reductions in seminal vesicle and ventral prostate weights .
These studies represent a fraction of the work suggesting that
endocrine disorders decrease anogenital distance in antenatally
exposed male animals.
hypothesis postulates that
Possible Associations Among Anogenital
Distance, Endocrine Disruption, and Genital
Anomalies in Humans
Human studies of endocrine disorders have yielded mixed
results. For example, in utero phthalate exposure may be
associated with reduced anogenital distance in male infants
[3••], whereas in utero exposure to degradation products of the
(DDT) does not appear to be associated with shortened human
male anogenital distance [7••]. To our knowledge, there are no
published data regarding the relationship of human anogenital
distance with hypospadias, and only one report has shown an
association between cryptorchidism and shortened anogenital
Preliminary data suggest that boys with hypospadias or
cryptorchidism feature reduced anogenital distance relative to
boys with normal genitals. We have conducted an institutional
review board–approved study of boys who have undergone
operations for urologic conditions at the University of
California San Francisco, and the Children’s Hospital of
Oakland (unpublished data). Boys with Tanner stage 2
development or higher, buried penis, chordee without
hypospadias, imperforate anus, exposure to corticosteroids or
growth hormone, or known syndromes were excluded.
Collected data included AASD and PASD [4•], age, height,
weight, race, and urologic diagnoses. To account for
prematurity, age at measurement was adjusted based on
gestational age at birth. Normal genitals were defined as the
absence of hypospadias, epispadias, and chordee, and complete
descent of both testes.
We compared parameters among boys with hypospadias,
cryptorchidism, or normal genitals, in addition to boys of
different races. One hundred and nine boys were enrolled in the
current study. Hypospadias, undescended testes, or normal
genitals were seen in 47, 32, and 40 boys (Table 2) [17–29].
The median weight of boys with hypospadias was less than that
of boys with normal genitals. There were no significant
differences among the groups in median age, height, body–mass
index (BMI); or percentiles for weight-for-age, height-for-age,
weight-for-height, and BMI-for-age. Boys of different races did
not have any differences in median values for any measured
Twenty measurements were performed by two of three
observers and correlated well. The median AASD and PASD of
boys with hypospadias, cryptorchidism, or normal genitals were
significantly different. The median AASD and PASD of boys
with hypospadias were shorter than those with normal genitals
by 19% and 30%, respectively (both P < 0.001). The median
PASD of boys with hypospadias versus cryptorchidism was
shorter by 29% (P < 0.001). The median AASD and PASD of
boys with cryptorchidism were not significantly shorter than
that of boys with normal genitals (P > 0.05).
Although AASD correlated best with weight, we found
that the AASD of boys with hypospadias versus normal genitals
was still shorter after adjusting for weight (P < 0.001). The
AASD of boys with hypospadias versus cryptorchidism was
also reduced (P = 0.0222). Finally, the AASD of boys with
cryptorchidism versus normal genitals was also shorter after
adjusting for weight (P = 0.0315).
We measured AASD and PASD in boys with hypospadias,
cryptorchidism, or normal genitals; we also examined possible
confounding factors. The median weight of hypospadiac boys
was lower than those with normal genitals (10.3 versus 14.5 kg;
P < 0.05). This was likely due to a trend for patients with
normal genitals to be older than patients with hypospadias
(median 25 months vs. 13.1 months, respectively; P = 0.097),
especially given that weight-for-age percentiles were similar
among boys with hypospadias, cryptorchidism, or normal
genitals (P = 0.46). There were also no significant differences
in median age, height, BMI, or percentiles for height-for-age,
weight-for-height, and BMI-for-age among boys with
hypospadias, cryptorchidism, or normal genitals.
In the cohort described herein, we did not measure
anogenital distance (the distance from the anus to the penopubic
junction). We and other investigators have preliminary data
suggesting that anogenital distance may feature higher inter-
rater reliability than AASD and PASD. Anogenital distance,
however, includes penile girth, a potentially confounding factor.
Finally, the most reliable measures of perineal length may or
may not be the best measures of endocrine disruption, if any.
Additional study is required to explore these issues.
Previous work has shown that analysis of covariance
(ANCOVA) of anogenital distance using weight as a covariate
is the best method to neutralize any effects of weight on
anogenital distance . Hence, in addition to KWANOVA
analyses, we performed ANCOVA and found that differences in
AASD persisted between boys with hypospadias and normal
genitals (P < 0.001). ANCOVA also demonstrated that after
correction for weight, boys with cryptorchidism had shorter
AASD than those with normal genitals (P = 0.0315). Therefore,
accurately normalized perineal lengths are shorter in boys with
hypospadias or cryptorchidism compared with those with
Because of insufficient prior data [14,15] and a low
number of African-American patients (n = 5), we were unable
to determine if the rates of hypospadias and cryptorchidism
among boys of different races were consistent with expected
frequencies. However, statistical analysis did not reveal a role
for race in models of AASD. Blind observers to the boys’
diagnoses were not possible because any hypospadias or
cryptorchidism was evident during perineal measurement. This
may have led to observer bias, although the magnitude of
observed differences in perineal length (30% in median PASD)
suggests that bias would not change overall findings.
Our data may feature selection bias, however. If the
patients we examined are not representative of boys with
hypospadias, cryptorchidism, or normal genitals, our findings
may be invalid. For example, not all boys with hypospadias or
cryptorchidism present for surgical correction. Nevertheless, we
believe that the current study drew from a diverse patient
population, and we avoided overly stringent exclusion criteria.
We excluded patients with buried penis because it is difficult to
locate the true penoscrotal junction in affected boys. Boys with
chordee but no hypospadias were excluded because chordee
may represent the mild end of the chordee–hypospadias
spectrum, and hence it is unclear how to best classify these
patients. Future studies will examine the anogenital distance of
boys with chordee.
Studies have measured perineal lengths using conscious
children [3••,4•,6,7••,16]. Such assessments can be difficult
because of intentional and unintentional resistance to
examination. In the current study, all measurements were
performed under anesthesia and we believe this permitted more
accurate assessment of perineal length. Inter-observer reliability
was high, with Lin’s correlation coefficients  of 0.8938 and
0.8815 for PASD and AASD, respectively. Prior work has
reported a correlation coefficient of 0.64 to 0.85 for male PASD
[4•, 7••], and 0.88 for male AASD [7••]. Because no boys in the
study underwent repeat surgery during the study interval, we
were unable to determine intra-observer reliability.
Another report on human AASD used an identical
definition as ours [7••], but median AASD for boys with normal
genitals in our study, 91 mm, differed from their median of 45.4
mm, likely because the age and weight of boys with normal
genitals in the current study (medians of 25 months and 14.5
kg) was greater than that of boys in the study by Longnecker et
al. (< 2 days, weight range 2.5-5.1 kg) [7••]. PASD has been
defined in the same fashion for multiple studies, and differences
are apparent, such as mean 44.5 mm (current study) versus 35.9
mm [3••], 21 mm [4•], and 19.1 mm (median) [7••]. Again, it is
difficult to draw broad conclusions from these findings because
of age and weight differences: 15.9 months, 10.5 kg [3••] and
less than 1 day, 3.01 kg [4•]. Defining the normative ranges and
relative importance of the various measures of perineal length
will require additional studies.
One boy in the current study had hypospadias and
undescended testes, and was placed in the hypospadias group
for statistical analysis. Switching this patient to the cryptorchid
group, or excluding the patient from analysis, did not alter
statistically significant findings. Restricting the definition of
normal genitals to phimosis or those undergoing circumcision
revisions, and hence eliminating patients with diagnoses such as
hernias, hydroceles, meatal stenosis, and vesicoureteral reflux,
also did not change statistically significant findings.
Because of insufficient power, we did not attempt to
correlate the precise severity of hypospadias or cryptorchidism
to perineal length. Ongoing work is addressing these
possibilities, which would provide additional indirect support
for the endocrine disruptor hypothesis as it relates to
hypospadias and cryptorchidism in humans.
Even if reduced perineal lengths in boys with hypospadias
are not due to endocrine disruption, at a minimum they
represent previously unrecognized anatomic abnormalities. To
our knowledge, this report is the first to describe a clinically
relevant association between
hypospadias in humans. Reduced anogenital distance in boys
with proximal hypospadias has implications for local tissue
anogenital distance and
flaps during surgical repair. Finally, shortened perineal length
in the setting of hypospadias and cryptorchidism may be a
subtle component of global
phenotypic changes in
In multiple animal species, endocrine disorders cause a variety
of perturbations in normal reproductive development, namely
cryptorchidism and hypospadias. More subtle, global alterations
in sexual differentiation, such as shortened anogenital distance,
may also result in animals exposed to endocrine disorders.
Evidence for endocrine disorders inducing hypospadias and
cryptorchidism in humans is weaker, but some data suggest that
human exposure to endocrine disorders, namely phthalates, is
associated with reduced anogenital distance. Finally, our
preliminary data indicate that human hypospadias and
cryptorchidism may be associated with shortened anogenital
distance. Further study is needed to corroborate or refute these
No potential conflicts of interest relevant to this article have been reported.
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