Transcript Cryptorchidism • One of the most common male developmental abnormalities • 27,000 orchidopexies annually in USA • 89% of untreated males with bilateral cryptorchidism develop.

Cryptorchidism
• One of the most common male
developmental abnormalities
• 27,000 orchidopexies annually in USA
• 89% of untreated males with bilateral
cryptorchidism develop azospermia
• Lifetime risk of neoplasia 2-3%
– 4 fold higher than average risk
Issues
•
•
•
•
Definitions & epidemiology
Normal testicular development and descent
Causes of cryptorchidism
Consequences
– Azospermia
– Increased risk for neoplasia
• Treatment
– Medical/hormonal
– Surgical
Definitions
• Cryptorchid: testis neither resides nor can be
manipulated into the scrotum
• Ectopic: aberrant course
• Retractile: can be manipulated into scrotum where
it remains without tension
• Gliding: can be manipulated into upper scrotum
but retracts when released
• Ascended: previously descended, then “ascends”
spontaneously
Epidemiology
• Frequency 3.4 % in term boys
• By 1 yo, incidence 0.8%
Is the incidence of
cryptorchidism increasing?
• Literature controversial
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Cryptorchidism, hypospadias, micropenis
Decreasing semen quality
Increasing testicular cancer
Increasing demand for assisted reproduction
• Impact of environmental xenoestrogens
– Herbicides, pesticides, PCBs, polystyrenes
• Environmental antiandrogens
– Linuron, vinclozolin, pp’DDE, polyaromatic
hydrocarbons
Risk Factors
Hjerkvist 1989
• IUGR, prematurity
– Incidence in premies 30%
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First-or second-born
Perinatal asphyxia
C-section
Toxemia of pregnancy
Congenital subluxation of hip
Seasonal (especially winter)
Issues
•
•
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Definitions & epidemiology
Normal testicular development and descent
Causes of cryptorchidism
Consequences
– Azospermia
– Increased risk for neoplasia
• Treatment
– Medical/hormonal
– Surgical
Testicular development
• 6 wk primordial germ cells migrate to
genital ridge
• 7 wk testicular differentiation
• 8 wk testis hormonally active
– Sertolis secrete MIF
• 10-11 wk Leydig cells secrete T
• 10-15 wk external genital differentiation
Testicular descent
• 5-8 wk processus vaginalis
– Gubernaculum attaches to lower epididymis
• 12 wk transabdominal descent to internal
inguinal ring
• 26-28 wk gubernaculum swells to form
inguinal canal, testis descends into scrotum
• Insulin-3 (INSL3) effects gubernacular
growth
INSL3
• Member of the insulin/relaxin superfamily
• Highly expressed in Leydig cells
• In mice, targeted INSL3 deletion associated
with bilateral cryptorchidism, abnl
gubernaculum development
INSL3
• Tomboc 2001
– DNA analysis of 145 cryptorchid males, 36 controls
– Found 2 mutations (2/145, 1.4%), several
polymorphisms
• Baker 2002
– DNA from 118 cryptorchid boys, 48 controls
– Several polymorphisms
– No specific mutations
• Important in descent but mutations an uncommon
cause of cryptorchidism
Germ cell maturation
• 8 wk: gonocytes (fetal stem cells)
• 15 wk: spermatogonia
• 3 mo of age: adult dark spermatogonia
(adult stem cells) appear and remain
– Neonatal surge in LH, FSH, T
• 4 yo: primary spermatocytes
• Puberty: spermatogenesis
Issues
•
•
•
•
Definitions & epidemiology
Normal testicular development and descent
Causes of cryptorchidism
Consequences
– Azospermia
– Increased risk for neoplasia
• Treatment
– Medical/hormonal
– Surgical
Low/absent GnRH
Kallmann’s
Prader Willi
Hypopituitarism
Hypothalamus
GnRH
Pituitary
FSH
Sertoli
MIF
LH
Leydig
Germ cells
Testosterone
5  reductase
Dysgenesis/anorchia
Testosterone biosynthetic problems
MIF deficiency/persistent Mullerian ducts
5  reductase deficiency
dihydrotestosterone
Androgen receptor
Post-receptor effects
Androgen resistance
Abnormal gonadotropins in
cryptorchid infants and boys
• Insufficient T response to hCG in 36.5%
(Forest 1979)
• Blunting of LH and FSH surge at 3 mo
(Gendrel 1980)
• Leydig cell hypoplasia in some
undescended testes (Hadziselimovic 1986)
Defective onset of meiosis at
4-5 yo?
• Normally see increase in urinary LH and
increased prominence of Leydig cells,
• Appearance of primary spermatocytes
• In cryptorchid males,
– Low urinary LH & FSH
– Impaired T response to hCG
– May indicate deficiency of HP-gonadal axis as
a cause of defective meiosis
Issues
•
•
•
•
Definitions & epidemiology
Normal testicular development and descent
Causes of cryptorchidism
Consequences
– Azospermia
– Increased risk for neoplasia
• Treatment
– Medical/hormonal
– Surgical
Impact on Fertility
• At bx, # spermatogonia/tubule prognostic for
subsequent fertility potential
– Bx without germ cells 33-100% risk of infertility
• Possible causes of subfertility
– Reduction in total # germ cells (already present in 1st
year of life)
– Defect in one or more steps in germ cell maturation
• Defective transformation of gonocytes into Ad spermatogonia
(Hadziselimovic 1986)
• Delayed disappearance of gonocytes
Incidence of Azospermia
Azospermia in normal population 0.4-0.5%
Unilateral
Bilateral
Untreated
13.6%
(10/73)
88.6%
(31/35)
Medically
treated
13.3%
(28/210)
32.0%
(46/142)
Surgically
treated
13.3%
(126/942)
46.4%
(224/484)
Hadziselimovic 2001
Chronological development of germ cells (#/cross
section)
germ cells/txs
5
4
3
UDT
CDT
2
1
0
3-7
n=15
8-12
n=15
13-18 19-25
n=12 n=15
age (mo)
Hadziselimovic 2001
29-60 <120
n=13 n=10
Ad/T
Number Ad spermatogonia/tubular cross-section from 0-9 yo
0.18
0.16
0.14
0.12
0.1
0.08
0.06
0.04
0.02
0
UDT
CDT
0.3 0.9 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5
Year
Hadziselimovic 2001
180
6
160
5
140
120
4
100
< 6 mo
6-24 mo
3
< 6 mo
6-24 mo
80
60
2
40
1
20
0
0
Age
# germ cells/tubular cross-section
1st
Normal in 6 mo, greatly decreased
Between 6-24 mo
Hadziselimovic 2001
Age
Ad
spermatogonia
No Ad
spermatogonia
Sperm/ejaculate (1x106)
If Ad spermatogonia present at orchidopexy,
Tended to have normal sperm count as adults
Abnormal germ cell deveopment
Huff 2001
• 767 boys with unilateral cryptorchidism
• Bilateral bx and orchidopexy between 0-9
yo
• 238 < 1 yo at orchidopexy
– Transformation of gonocytes into Ad
spermatogonia
• 529 2-9 yo at orchidopexy
– Onset of meiosis
4.5
4
3.5
3
2.5
germ
cells/tubule 2
1.5
1
0.5
0
UDT
CDT
1
3
5
7
9
11
month
Total germ cell counts significantly higher in undescended testes, p=0.024
Huff 2001
11
9
7
5
3
UDT
CDT
1
0.45
0.4
0.35
0.3
gonocytes/ 0.25
0.2
tubule
0.15
0.1
0.05
0
month
Total gonocyte counts significantly higher in undescended testes, p<00005
Huff 2001
Adult dark spermatogonia
0.25
0.2
0.15
UDT
CDT
0.1
0.05
0
1
3
5
7
9
11
month
Total adult dark spermatogonia counts significantly lower in undescended testes,
p<00005, Huff 2001
Boys < 1 yo
• Gonocytes failed to disappear
• Adult dark spermatogonia failed to appear
• Indicates defect in germ cell maturation and
failure to establish an adequate adult stem
cell pool
Boys 2-9 yo
• In undescended testes
– Primary spermatocyte counts lower (p<0.0005)
failed to appear in undescended testes
Appeared in only 19% of contralat descended testes
– Total germ cell counts lower (p<0.0005)
– Adult dark spermatogonia lower (p<0.0005)
• Indicates defect in onset of meiosis
– Which normally occurs at 4-5 yo
• Similar, less severe changes in contralateral
descended testes
Abnormal Epididymal Growth
de Miguel 2001
• Decrease in differentiation of each segment
• Decreased size of efferent and epididymal ducts
• Decreased epithelial height, muscular wall height,
& lumen of epididymis
• Cryptorchid epididymis grows more slowly during
transition to puberty, smaller in adult males
• Suggests a primary congenital defect of testis
• Implies surgical descent would not completely
reverse these changes
Increased risk of neoplasia
• Cortes 2001: 1638 testicular samples from
1335 patients (23% bilateral, 77%
unilateral)
• Mean age @ surgery 11.7 yo (0.1-18.9 yr)
• 1 invasive germ cell tumor
• 6 carcinoma in situ
• 1 Sertoli cell tumor
Neoplasia & cryptorchidism
• 3 neoplasms in intra-abdominal testes
• 4 neoplasms in boys with abnormal external
genitalia
• 2 neoplasms in boys with known abnormal
karyotype
• Risk of neoplasia 5% with intraabdominal
testes, abnormal external genitalia or
abnormal karyotype (Cortes 2001)
Issues
•
•
•
•
Definitions & epidemiology
Normal testicular development and descent
Causes of cryptorchidism
Consequences
– Azospermia
– Increased risk for neoplasia
• Treatments
– Medical/hormonal
– Surgical
Treatments
• Hormonal
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–
–
hCG
GnRH
hMG
Combined (hCG & GnRH)
• Surgical
Hormonal Therapy
• hCG since 1930
• GnRH since 1974 (IM) and 1975
(intranasal) (Europe)
• Variable rates of success
– hCG 0-55%
– GnRH 9-78%
Confounding Variables in Data
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Inclusion/exclusion of retractile testes
Variable ages of treatment
Randomized or not
Different dose regimens and durations
Original testicular position not documented
in all studies
• Small patient numbers
hCG vs GnRH: multicenter trial
• 330 boys (?ages)
• Randomized to
– hCG 100 IU/kg IM twice weekly x 3 wk
– GnRH 200 ug intranasal TID x 28 d
– Placebo intranasal TID x 28 d
• Success if both testes located at bottom of
scrotum after treatment
Changes in position in boys with bilateral cryptorchidism after
treatment. Christiansen 1992
Not palp
Placebo
GnRH
hCG
12
6 1
8
8
2
1
2
70
31
Inguinal
5
Suprascrotal
2
86
69 1
6
14 1
High scrotal
1
3
4
2
70
46
8
2
5
21
4 6
15
4 6 1
15
5
7
2
4
17
6
5
1
12
3
1
5
3
5
1
12
11
6
Scrotal
1
2
7 3
Rates of descent of the undescented testes following treatment.
Christiansen 1992.
25
20
15
Bilateral
Unilateral
%
10
5
0
Placebo
Bilateral: p=0.0016
Unilateral: p=0.013
GnRH
hCG
A review & meta-analysis of
hormonal treatment of
cryptorchidism (Pyorala 1995)
• Reports from 1958-1990, in English
• Primary treatment with GnRH or hCG
• Excluded articles not documenting final
testicular position
• Durations of treatment
– GnRH 1 day – 4 wk
– hCG 1 wk – 12 mo
Review & meta-analysis
• 33 studies including 3282 boys, 4524 undescended
testes
• RCTs (n=11) included 872 boys, 1174
undescended testes
• Meta-analysis only on RCTs that compared GnRH
vs placebo (n=9 trials)
– Risk ratio for descent after GnRH 3.21 (1.83-5.64)
(p<0.001)
– 4 trials excluded retractile testes, risk ratio 2.57 (1.394.74) (p<0.01)
Mean success rate (%) for treatment in combined RCTs comparing
hGC and GnRH with placebo. Pyorala 1995
25
20
15
Placebo
hCG
GnRH
%
10
5
0
# Trials
9
2
11
Testes
472
148
554
Mean success rate (%) for treatment in RCTs exluding retractile testes, comparing
hGC and GnRH with placebo. Pyorala 1995
20
18
16
14
12
% 10
8
6
4
2
0
Placebo
hCG
GnRH
# Trials
4
2
5
Testes
308
148
335
Mean success rates (%) by original location, includes both RCTs and
nonRCTs after GnRH and hCG. Pyorala 1995
60
50
40
Abdominal
Inguinal
Prescrotal
High srotal
% 30
20
10
0
# trials
17
21
14
# testes
907
1430 295
4
67
Mean success rates (%) of hormonal treatment (GnRH or hCG) in combined
RCTs in boys under 4 yo vs boys > 4 yo. Pyorala 1995 p=NS
25
20
15
Placebo
Homone
%
10
5
0
<4yo
>4yo
# trials
2
2
3
4
# testes
48
49
167
267
Long term outcomes
• 5/11 randomized GnRH trials
• 24% (13-35%) ascended/relapsed
• Conclusions:
– GnRH more effective than placebo
– hCG seems effective, but not as much data
Combined GnRH and hCG
Giannopoulous 2001
• 2467 boys with 2962 cryptorchid or gliding
testes
• GnRH nasal spray 1.2 ug QD x 4 wk
• hCG 5 doses (by age) at 2 d intervals
• 59% in scrotum after combined rx
4 different regimes
Bertelloni 2001
• 155 boys 10-48 mo with unilateral inguinal
testis
• 1. hCG 500 IU/wk (<2yo), 1000 IU/wk
(>2yo)
• 2. hCG as in 1 + hMG 75 IU/wk x 6 wk
• 3. GnRH 1200 ug/d x 28 d
• 4. GnRH as in 3, + hCG 1500 IU/wk x 3 wk
Bertelloni 2001 cont.
• Overall success rate 19.3% (30/155)
• No significant differences between regimes
• Relapse 23.3% (7/30)
– No significant difference between regimes
When to treat?
Hamza 2001
• As spontaneous testicular descent closely
related to postnatal LH and T surges,
• In term boys, 4 mo
• In premies, 6 mo
Impact of age on treatment
success
• Job 1982: success with hCG twice as high
in 3-4 yo than in boys < 3 yo
• Hagberg 1982: highest success with GnRH
in 2-5 yo
• De Muinck Keizer-Schrama 1986: most
success with GnRH in 5-12 yo
• Pyorala 1995: no significant differences < 4
yo vs > 4 yo
When to operate?
• Lee 2002
• Inverse correlation between age at surgery
and T
• Inverse correlation between body wt and T
• Direct correlation between T and sperm
density, motility, morphology
• Indicates direct relationship between
spermiogenesis and T in cryptorchid men
• No differences in mean free T, T, LH between pts
and controls
• No differences in time to conception in fertile
cryptorchid men vs controls
• Suggests that orchidopexy later in childhood assoc
with subclinically depressed Leydig cell function
• May result in subotpimal hormonal milieu for
adult reproduction
Is further treatment after surgery
indicated?
• Subfertility correlates with reduced total
germ cell counts
• Defects in germ cell maturation associated
with blunting of normal surges LH/FSH
• Prepubertal treatment with GnRH could
theoretically trigger normal germ cell
maturation & proliferation
Hormonal treatment for
subfertility of cryptorchidism
Huff 2001
• 12 boys (7 mo – 12 yo) with cryptorchidism
& poor prognosis for fertility (<0.21 germ
cells/tubule)
• Treated with Naferelin 200 ug biweekly x 6
mo after orchidopexy
• Biopsy 5 mo after Naferelin completed (214 yo)
• Improvement if 2nd bx > 1 category
Hormonal treatment for
subfertility of cryptorchidism
Huff 2001
• 8/12 (67%) showed improvement in total germ
cell counts in one or both testes
• No significant change if patients
– Had no germ cells initially
– Were older at treatment
• 8/18 (44%) undescended testes improved
• 5/6 (83%) contralateral descended testes improved
• Naferelin induced improvement in 75% of patients
Erythropoietin and germ cells
• Cortes 2001
• 2 boys (6 mo, 21 mo) with renal function
impairment
• Epo 100 IU/kg SQ weekly x 3 mo before
orchidopexy for inguinal cryptorchidism
• # spermatogonia unusually high (& normal)
compared to 698 controls
Possible mechanisms
• Stimulation of T production
– ?direct on Leydig cells
• Direct effect on germ cell proliferation and
antiapoptotic signalling by blocking p53gene mediated apoptosis (as seen in
erythropoiesis)
• Clinical trial ongoing
Issues
•
•
•
•
Definitions & epidemiology
Normal testicular development and descent
Causes of cryptorchidism
Consequences
– Azospermia
– Increased risk for neoplasia
• Treatment
– Medical/hormonal
– Surgical