Full text of DOI:10.1016/S0022-5347(05)67806-8

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022-5347/00/1633-0792/0
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THE JOURNAL OF UROLOGY
Vol. 163, 792–795, March 2000
Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.®
Printed in U.S.A.
TESTIS BIOPSY FINDINGS IN THE SPINAL CORD INJURED PATIENT
SEAN P. ELLIOTT, FRANCISCO OREJUELA, IRVIN H. HIRSCH, LARRY I. LIPSHULTZ,
DOLORES J. LAMB* AND EDWARD D. KIM†
From the Scott Department of Urology and Department of Cell Biology, Baylor College of Medicine, Houston, Texas, and the Department
of Urology, Jefferson Medical College, Philadelphia, Pennsylvania
ABSTRACT
Purpose: Azoospermia after electroejaculation in spinal cord injured men may be due to
testicular failure or obstruction. These men can initiate pregnancy with assisted reproductive
techniques, such as intracytoplasmic sperm injection, but only if sperm are present in the testis
biopsy. We analyzed the histopathology of testis biopsies from spinal cord injured men and
assessed whether patient factors were predictive of testis biopsy pathology.
Materials and Methods: A total of 50 paraplegic men undergoing testis biopsy were divided into
2
groups based on normal or abnormal testis histopathology. Patient age, post-injury years, level
of lesion, hormonal status and semen analysis results were compared.
Results: Spermatogenesis was normal in 28 of the 50 patients. Hypospermatogenesis was
exhibited in 15, maturation arrest at the spermatid stage in 6 and maturation arrest at the
spermatocyte stage in 1 of the 22 abnormal cases. Nevertheless, mature sperm were identified in
4
3 of 50 biopsies (normal spermatogenesis and hypospermatogenesis). Men with normal sper-
matogenesis had better forward progression of sperm and a higher testosterone-to-luteinizing
hormone ratio. Otherwise, there was no statistically significant correlation between study vari-
ables and testis biopsy results. No factors were predictive of testis biopsy histopathology.
Conclusions: The documentation of mature sperm in 43 of 50 biopsies from spinal cord injured
patients suggests that a high rate of sperm retrieval is possible using testicular sperm extraction
if sperm cannot be retrieved from the ejaculate. With intracytoplasmic sperm injection tech-
niques the majority of spinal cord injured men retain fertility potential, even if azoospermic
following electroejaculation.
KEY WORDS: testis, biopsy, electric stimulation, spinal cord injuries, spermatogenesis
Spinal cord injured patients, typically young men, repre- obtained by testicular sperm extraction (TESE).7, 8 Thus, we
sent the largest physical medicine and rehabilitation popu- sought to identify factors predictive of testicular biopsy find-
lation with fertility related disorders. Although 3% to 20% of ings to help identify spinal cord injured patients who would
these men can ejaculate with self-stimulation, this ability be good candidates for TESE and subsequent IVF-ICSI.
tends to be unpredictable and is rarely effective to initiate
1
pregnancy. In 85% to 97% of these men loss of ejaculatory
2
capability is permanent. Rectal probe electroejaculation and
MATERIALS AND METHODS
vibratory penile stimulation provide an approach to obtain
Study design and subjects. A prospective analysis was per-
formed based on a cohort of 50 spinal cord injured patients who
semen. However, even when semen is produced azoospermia
is not uncommon and asthenospermia is common. The cause
presented to our tertiary care centers for evaluation of infertil-
of poor semen quality following electroejaculation is unclear.
ity and underwent electroejaculation with semen analysis. A
We previously demonstrated that the electroejaculation
subset of patients cared for by one of us (I. H. H.) underwent
procedure has no effect on sperm motility or forward progres-
3
testis biopsy regardless of semen analysis results and the re-
mainder underwent biopsy only if the sample indicated oligo-
spermia or azoospermia. Patients were categorized into 2
groups based on normal or abnormal testis histology, and de-
mographic characteristics and laboratory values were com-
pared. Study variables consisted of patient age, post-injury
sion in vitro. Brackett et al demonstrated that the seminal
plasma of spinal cord injured men may be detrimental to
4
sperm. Poor sperm quality after electroejaculation of spinal
cord injured patients has resulted in low fertilization and
pregnancy rates, despite use of in vitro fertilization (IVF) or
intrauterine insemination.5 However, with assisted repro-
ductive techniques, such as intracytoplasmic sperm injection years, level of injury, serum follicle-stimulating hormone (FSH)
(
ICSI), it is now possible to achieve fertilization more effec- (normal 4 to 10 ng./ml.), serum luteinizing hormone (LH) (nor-
tively using sperm even from a specimen obtained by elec- mal 6 to 19 mIU/ml.), total serum testosterone (normal 200 to
6
troejaculation. Additionally, even if the azoospermic spinal 1,000 ng./dl.), testosterone-to-LH ratio and semen analysis, in-
cord injured male has only a few mature sperm on testis cluding volume, sperm density, sperm motility and forward
biopsy, fertilization is still possible with ICSI using sperm progression (0 to 4). Serum hormones were measured within 6
months of biopsy. Some patients received several trials of elec-
troejaculation and, therefore, the specimen with the best overall
Accepted for publication October 1, 1999.
Supported by National Institutes of Health Grant RO1.HD30155. semen analysis (highest sperm density, motility and forward
*
Financial interest and/or other relationship with Humagen, Na- progression) was considered representative.
tional Institutes of Health and CMA.
Electroejaculation technique. The electroejaculation prep-
†
American Foundation for Urologic Disease Scholar and recipient
9
aration and procedure have been described previously.
of the American Society of Reproductive Medicine Ortho Young In-
vestigators Award.
Briefly, rectal probe stimulations were delivered with a
792

TESTIS BIOPSIES OF SPINAL CORD INJURY PATIENTS
793
G & S Model 12† electroejaculator. An increasing series of difference in serum FSH, LH or total testosterone between
voltages was delivered, using 2 stimulations for each voltage, the 2 groups. The testosterone-to-LH ratio was significantly
with each stimulation lasting approximately 2 to 4 seconds. If higher in group 1 patients (table 1). Sperm density and
the patient had not ejaculated at a maximum of 10 V., then 3 motility in the antegrade fraction were not statistically dif-
stimulations were used at each voltage before proceeding to ferent between groups. Forward progression was signifi-
the next higher voltage. Most patients ejaculated at less than cantly higher in group 1 (table 1). All data points were avail-
2
0 V. and less than 50 stimulations but occasionally up to 30 able in 22 cases. Multiple logistic regression analysis
V. were required. Antegrade and retrograde samples were revealed no variable to be predictive of testis biopsy outcome
collected. Only the antegrade semen analysis is reported as (table 2).
consistent assessment of retrograde volume and sperm den-
sity was difficult.
DISCUSSION
Testis biopsy. The testis biopsy procedure has also been de-
scribed previously.10 During the procedure patients received no
Our significant practical finding is that the majority of
or general anesthesia depending on the completeness of the spinal cord injured men presenting for electroejaculation
spinal cord lesion. After a 1 to 2 cm. incision was made through have mature sperm on testis biopsy. Of 50 patients 43 had
the parietal tunica vaginalis, the tunica albuginea was incised mature sperm on histological examination of the testicular
for approximately 5 mm. with a No. 11 scalpel blade. Gentle tissue and this ratio was no different for those with severe
pressure on the testicle extruded a small amount of testicular oligospermia or azoospermia (less than 1 million sperm per
parenchyma, which was carefully excised with fine, sharp scis- ml., 9 of 11 patients). The clinical application of this obser-
sors and placed promptly in an appropriate fixative or processed vation is that even if electroejaculation results in an
first for cytological analysis. After hemostasis was obtained the azoospermic semen specimen patients should be counseled
tunica albuginea and layers of the scrotal wall were closed with that they may be good candidates for TESE with ICSI, or
fine absorbable running suture. Based on standard pathological sperm retrieval from the epididymis or vas deferens if there
interpretations of the hematoxolin and eosin sections, biopsies is obstruction.11 Consistent with previous studies of spinal
were classified as Sertoli-cell-only, maturation arrest- cord injured men we found no factor to be predictive of testis
spermatocyte stage (spermatocytes but no spermatids), matu- biopsy findings. Forward progression and testosterone-to-LH
ration arrest-spermatid stage (spermatids but no mature sper- ratio, although significantly higher in men with normal find-
matozoa), hypospermatogenesis or normal spermatogenesis. ings, were not predictive of testis biopsy results. Therefore, if
Hypospermatogenesis indicates that all stages of spermatogen- other methods of sperm retrieval have failed, TESE with
esis, including mature sperm, are present but the relative num- ICSI may be pursued regardless of the level of lesion, patient
bers of cells are decreased.
age, time since injury, hormone concentrations and semen
Statistical analysis. Statistical analysis was performed in analysis.
collaboration with a professional biostatistician using com-
Our results demonstrate that a higher proportion of spinal
puter software. Data are presented as mean plus or minus cord injured men possess at least some mature spermatozoa
standard error unless otherwise stated. Results for continu- (hypospermatogenesis or normal) on testis biopsy than pre-
ous variables were compared between groups using the un- viously reported. Stemmermann et al reported normal find-
paired Student t test or Mann-Whitney rank sum test when ings in 6 of 16 spinal cord injured patients, hypospermato-
normalcy failed. Using a contingency table of independence a genesis in 3, various phases of maturation arrest with no
chi-square test was performed for the categorical variable apparent spermatozoa in 6 and the Sertoli-cell-only syn-
(
level of lesion). Predictability of testis biopsy results using drome in 1.12 Bors et al found normal spermatogenesis in 3 of
demographic data, serum hormones and semen analyses was 34 paraplegic men, hypospermatogenesis in 17 and varying
assessed by multiple logistic regression analysis.
degrees of maturation arrest in the remaining 14, including 1
1
3
with the Sertoli-cell-only syndrome. Leriche et al reported
that 27 of 54 biopsies in spinal cord injured men showed
tubular atrophy and maturation arrest, with the other 50%
demonstrating atypical findings of normal spermatogenesis
but obstruction of the tubules and hyperplasia of the Sertoli
RESULTS
Patient age at biopsy was similar between the 2 groups.
Similarly, the delay between spinal cord injury and testis
biopsy, and the level of spinal cord injury between groups
was not significantly different (table 1). Spermatogenesis
was normal in 28 men (group 1). Hypospermatogenesis was
noted in 15 (30%), maturation arrest-spermatid stage in 6
1
4
cells. A smaller study by Perkash et al yielded results
similar to ours as spermatogenesis was normal in 6 of 13
spinal cord injured patients (46%) and the remainder had
1
5
hypospermatogenesis.
(
12%) and maturation arrest-spermatocyte stage in 1 (2%) of
A possible explanation for our higher frequency of mature
sperm is that we specifically sought to identify even small
numbers of mature sperm. This distinction is important be-
the 22 abnormal cases (group 2). There was no significant
†
G & S Instrument Co., Duncanville, Texas.
TABLE 1. Testis biopsy results versus study parameters
No.
Group 1
No.
Group 2
Normal
Abnormal
p Value
Pt. demographics:
Mean age Ϯ SE
31.6 Ϯ 1.4
8.8 Ϯ 1.4
10 Cervical, 16 thoracic, 2 lumbar
24
23
28
32.1 Ϯ 1.3
8.7 Ϯ 1.8
6 Cervical, 12 thoracic, 3 lumbar
20
17
21
0.730
0.853
0.556
Mean post-injury yrs. Ϯ SE
No. lesion level
Mean serum hormones Ϯ SE:
FSH (ng./ml.)
6.5 Ϯ 1.1
7.4 Ϯ 1.9
464.7 Ϯ 35.5
168.6 Ϯ 30.2
25
25
25
24
10.0 Ϯ 2.5
14.4 Ϯ 3.6
450.8 Ϯ 44.7
84.4 Ϯ 21.7
19
17
17
16
0.530*
0.096
0.807
0.029
LH (mIU/ml.)
Testosterone (ng./dl.)
Testosterone-to-LH ratio
Mean semen analysis Ϯ SE:
Density (million sperm/ml.)
179.2 Ϯ 75.2
13.3 Ϯ 3.1
2.0 Ϯ 0.2
19
19
19
75.0 Ϯ 44.1
12.5 Ϯ 4.1
1.1 Ϯ 0.2
16
17
14
0.552*
0.877
0.004
%
Motility
Forward progression
*
Mann-Whitney rank sum test.

7
94
TESTIS BIOPSIES OF SPINAL CORD INJURY PATIENTS
TABLE 2. Multiple logistic regression analysis
retrieval, which is productive in the majority. However, at a
tertiary care facility the spinal cord injured patient often
presents with azoospermia after assisted ejaculation. We
demonstrated that the majority retain fertility potential,
even when azoospermia is found. Our biopsy results suggest
that spinal cord injured men will likely have sperm on TESE,
despite the indication of testicular failure based on semen
Parameter
p Value
Pt. demographics:
Age
0.3928
0.6161
0.9190
Post-injury yrs.
Lesion level
Serum hormone concentrations:
FSH
0.2671
0.0714
0.5575
0.1143
7
, 8
analysis and hormone concentrations.
Although some
LH
Total testosterone
Testosterone-to-LH ratio
Semen analysis:
Density
azoospermic spinal cord injured patients had obstruction, the
standard care for most is sperm retrieval rather than correct-
ing the cause of the obstruction. Thus, spinal cord injured
men should be counseled about reproductive possibilities us-
ing TESE with ICSI.
0.2014
0.2600
0.1540
Motility
Forward progression
CONCLUSIONS
cause today only a few sperm are required to initiate a
pregnancy with ICSI. Interestingly, in contrast to some ear-
lier studies but in agreement with Perkash et al we found
that testis biopsies in spinal cord injured men rarely demon-
strated maturation arrest at the spermatocyte stage, and
Testis histopathology in the spinal cord injured patient is
commonly normal or hypospermatogenic. Maturation arrest
was rare, and the Sertoli-cell-only syndrome was not found in
our series. Sperm can be retrieved from the majority of spinal
cord injured men using a combination of vibratory stimula-
tion and electroejaculation. However, vasal aspiration or tes-
tis biopsy is indicated for patients who do not produce sperm
with these procedures. If mature sperm can be found on testis
biopsy in most spinal cord injured patients as in ours, TESE
with ICSI offers those with electroejaculation failure an im-
portant alternative means of fathering a biological child.
1
5
that the Sertoli-cell-only syndrome was nonexistent. In-
stead, biopsies from some spinal cord injured men were char-
acterized by a marked decrease in sperm production, sug-
gesting a difference in pathogenesis between testis failure
due to spinal cord injury and causes seen in otherwise
healthy but infertile men. A possible etiology of testis histo-
pathology particular to spinal cord injured men is testicular
hyperthermia.16
Electroejaculation Study Group members Stanton Honig,
Dana Ohl, Steven Shaban, Samuel Thompson and Michael
Witt contributed to the database.
Previous evaluations of various sex hormones in spinal
cord injured patients have yielded a variety of findings, from
normal serum concentrations to chronic elevations of LH,
FSH and testosterone.1
3, 15, 17, 18
No correlation in other series
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