REVIEWS

A step-wise approach to sperm retrieval

in men with neurogenic anejaculation
Mikkel Fode, Dana A. Ohl and Jens Sønksen
Abstract | Normal fertility is dependent on intravaginal delivery of semen through ejaculation. This process
is highly dependent on an intact ejaculatory reflex arc, which can be disrupted through any type of trauma or
disease causing damage to the CNS and/or peripheral nerves. Neurogenic anejaculation is most commonly
associated with spinal cord injury. This aetiology is especially relevant because most men with spinal cord
injuries are injured at reproductive age. Assisted ejaculation in the form of penile vibratory stimulation is the
first choice for sperm retrieval in such patients because it is noninvasive and inexpensive. In patients in whom
vibratory stimulation fails, electroejaculation is almost always successful. When both methods of assisted
ejaculation are unsuccessful, sperm retrieval by aspiration from either the vas deferens or the epididymis,
or by testicular biopsy or surgery are reasonable options. In such cases the most inexpensive and least
invasive methods should be considered first. The obtained semen can be used for intravaginal or intrauterine
insemination or in vitro fertilization with or without intracytoplasmic sperm injection.
Fode, M. et al. Nat. Rev. Urol. advance online publication 20 October 2015; doi:10.1038/nrurol.2015.241

Introduction
Naturally, male fertility relies completely on the produc-
tion of sperm in the testis. This process is tightly con-
trolled by hypothalamic and pituitary hormones and by
local paracrine factors, which are the subject of an abun-
dance of andrological and endocrinological research.
However, normal reproductive function is not only
dependent on adequate sperm production, but also on
the transportation and intravaginal delivery of sperm
through ejaculation. The ejaculatory reflex is highly
dependent on neurological integrity of the spinal cord
and the pelvic floor, therefore, ejaculatory function can be
severely compromised in men with neurological diseases.
In the most severe cases, neurological diseases or injuries
result in anejaculation.1 The term ‘anejaculation’ describes
a complete lack of both antegrade and retrograde ejacu-
lation, leading to male infertility even when associated
with sufficient sperm production. The most common
Department of Urology, cause of neurogenic anejaculation is spinal cord injury
Roskilde Hospital, (SCI), which occurs predominantly in young men who
Koegevej 7‑13,
DK‑4000 Roskilde, might wish to start a family, meaning that n­eurogenic
Denmark (M.F.). a­nejaculation is of major clinical significance.2–5
Department of Urology,
University of Michigan,
In spite of the existence of inexpensive and non­invasive
1500 East Medical methods to induce ejaculation and thereby retrieve
Center Drive, Box 0330, sperm for reproductive purposes in these patients, com-
Ann Arbor, MI 48108,
USA (D.A.O.). plicated and expensive surgical sperm retrieval methods
Department of Urology, are often employed as first-line treatment.6 This missed
Herlev Hospital,
University of
Copenhagen, Competing interests
Herlev Ringvej 75,
M.F. declares that he has acted as a consultant and speaker
DK‑2730 Herlev,
Denmark (J.S.).
for Astellas, Eli Lilly and Menarini. D.A.O. has acted as a
consultant for Pfizer and a speaker for Eli Lilly. J.S. has acted as
Correspondence to: a consultant and speaker for Coloplast, Eli Lilly and Menarini
M.F. and as a speaker for Astellas, and board member and
mikkelfode@gmail.com shareholder in Multicept, Denmark.
opportunity is especially unfortunate as the sperm
yield from such methods is generally lower than that
from assisted ejaculation and, therefore, automati-
cally commits couples to undergoing complicated and
e­xpensive assisted reproductive techniques (ART).
In this Review, we will provide an overview of the
mechanisms of normal ejaculation and explain how
anejaculation can arise from neurological damage. We
will then describe available techniques for assisted ejacu-
lation and surgical sperm retrieval in order to provide
a stepwise algorithm for treating men with neurogenic
anejaculation, starting with the most cost-effective and
least invasive options.
Ejaculation in neurologically intact men
Ejaculation is a physiological response to tactile sexual
stimulation. During sexual activity, sensory signals to the
glans penis are transmitted through the dorsal penile nerve
and, subsequently, through the pudendal nerve to reach
spinal cord centres at the thoracolumbar and sacral levels,
where they trigger the ejaculatory reflex once an excitatory
threshold is reached (Figure 1). In addition, ascending
signals reach higher centres in the CNS; however, their
roles in the ejaculatory process are not well known and
are likely to be of only minor importance.7,8 Technically
the process of ejaculation consists of two separate events:
seminal emission and the projectile phase of ejaculation.
Seminal emission denotes the phase during which
mature sperm cells from the ampulla of the vas deferens
and seminal fluid from the prostate and seminal vesicles
are transported to the posterior part of the urethra. This
process is mediated by sympathetic nervous input from
the T10–L2 regions of the spinal cord, which induces

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REVIEWS
Key points
■■ Any type of trauma or disease causing damage to the CNS and/or the
peripheral nerves in, and around the pelvic floor can cause anejaculation
■■ Penile vibratory stimulation (PVS) constitutes the cheapest and least invasive
method of inducing ejaculation
■■ In patients in whom PVS fails, electroejaculation has proved almost universally
successful
■■ Surgical sperm retrieval should be reserved strictly for patients in whom
assisted ejaculation fails
■■ The method of assisted reproductive technique should be chosen primarily
based on the total motile sperm count
■■ In selected cases, home insemination by the infertile couple themselves is
feasible, by means of PVS and intravaginal self-insemination
coordinated peristaltic contractions of smooth muscle
cells in the involved organs.9,10 Simultaneously, the same
nerve fibres induce contraction of the internal urethral
sphincter, thus preventing the ejaculate from flowing
into the bladder (retrograde ejaculation).9,11 The second
phase of ejaculation is controlled by somatic nerve fibres
from spinal segments S2–S4 and begins once the ejacu-
late has reached the urethra. Here the external urethral
sphincter relaxes while rhythmic peristaltic contrac-
tions of the periurethral and pelvic floor muscles moves
the ejaculate through the urethra and causes a pulsatile
projectile ejaculation.
Neurogenic ejaculatory dysfunction
Disruption of the reflex arc can result in complete
anejacu­lation, which is defined as an absolute lack of
ejaculate with normal sexual stimulation as a result
of complete failure of the emission phase of ejaculation.
In less severe cases, neurogenic ejaculatory dysfunction
presents as delayed ejaculation or retrograde ejaculation.
As the name implies, delayed ejaculation denotes a con-
dition in which ejaculation can still occur at a higher
threshold of sexual stimulation than usual.12
In the pathogenesis of retrograde ejaculation, most of
the reflex arc is functioning, but closure of the internal
urethral sphincter fails. This sphincter failure means
that the ejaculate begins to flow towards the bladder as
soon as it reaches the urethra and that additional fluid is
pushed backwards as a consequence of the periurethral
and pelvic floor muscle contractions, which are supposed
to induce the projectile ejaculatory phase.13 The condi-
tion is suspected in patients presenting with a reduced
(or absent) ejaculate in combination with cloudy urine
following sexual activity. Diagnostic confirmation is
obtained by postejaculatory examination of the urine
for the presence of spermatozoa.12 In patients with mild
cases of retrograde ejaculation, the condition can be tem-
porarily reversed by sympathomimetic medications such
as imipramine, which help contract the internal urinary
sphincter.14–16 In patients whose retrograde ejaculation
is refractory to such treatment, sperm can be harvested
from the bladder following ejaculation.17
Causes of neurogenic anejaculation
Although no reliable comparative data exist, SCI is
considered the most common cause of neurogenic
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anejaculation. Less than 10% of men with SCI are able to
ejaculate through normal sexual intercourse or mastur­
bation.18 However, in essence, any type of trauma or
disease causing damage to the CNS and/or the peripheral
nerves in and around the pelvic floor can cause anejacu­
lation. Relevant CNS disorders include congenital spinal
abnormalities, transverse myelitis, vascular spinal inju-
ries, and multiple sclerosis.19–21 The extent of ejaculatory
problems in these groups of patients depends on the loca-
tion and extent of disease, but generally resembles that
observed with SCI.14 Other potential causes of neuro­
genic anejaculation include pelvic trauma or surgery,
which can damage peripheral nerves, as well as peri­aortic
surgery and retroperitoneal lymph node dissection,
which can damage the crucial sympathetic ganglia or
arising neurones.22,23 Retroperitoneal lymph node dissec-
tion as part of testicular cancer treatment is particularly
important, as many of these patients are of reproductive
age; nerve-sparing procedures should be used whenever
possible. However, with large tumour burdens, nerve
sparing is not always feasible and the risk of subsequent
ejaculatory dysfunction remains high in such patients.24
Poorly controlled diabetes mellitus can eventually
cause peripheral neuropathy, which can be associ-
ated with a gradual decline in ejaculatory function.25
Approximately 40% of men with diabetes mellitus type 1
are affected by some degree of ejaculatory dysfunc-
tion.26 Symptoms usually start as retrograde ejaculation
and/or delayed ejaculation and can progress to frank
a­nejaculation over time.27
A step-wise approach to sperm retrieval
Treatment of anejaculation is only warranted in cases
when the patient desires to father children and the goal is
to obtain sperm for self-insemination or use in ART. As
with retrograde ejaculation, anejaculation caused by mild
neurological disorders can sometimes be treated with
sympathomimetic agents, although results are generally
poor owing to the severity of the neurological damage.15
However, in most patients, sperm can be retrieved using
either assisted ejaculation or surgi­cal sperm retrieval. As
a basic rule, the clinician should choose the treatment
which produces the highest sperm yield by the least
i­nvasive and most inexpensive method (Figure 2).
Assisted ejaculation
Penile vibratory stimulation
Penile vibratory stimulation (PVS) has been used
to induce ejaculation in men with SCI since at least
the 1980s, when Brindley published the first report
on the subject.28 With this method, a medical vibrator is
used to mechanically activate the dorsal penile nerve and
with sufficient stimulation the signal will reach the ejacu-
latory centres of the spinal cord, thereby activating the
efferent limb of the ejaculatory reflex.29,30 Early success
rates of PVS were generally low and in the early 1990s it
was discovered that the poor outcomes were likely caused
by discrepancies between manufacturers’ specifications
and the actual vibrator outputs concerning frequen-
cies and peak-to-peak amplitudes.31 A precise vibratory
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T10
T11
Seminal emission
T12 Motor innervation of
seminal vesicles,
L1 prostate, bulbourethral
gland and vas
L2 deferens epididymis)
L3
L4
L5
S1
S2 Ejaculation
Pudendal nerve Contraction of bulbo-
S3 cavenosus, ischiera-
vernosus muscles
Dorsal penile nerve S4 and pelvic floor
Sexual stimulation
Figure 1 | Schematic drawing of the ejaculatory reflex. The afferent limb of the
ejaculatory reflex is activated when sensory signals are transmitted through the
Nature Reviews | Urology
dorsal penile nerve and the pudendal nerve to reach spinal cord centres. Once an
excitatory threshold is reached, the efferent limb is activated, consisting of
sympathetic nerves from T10–L2, which induce seminal emission, and somatic
nerves from spinal segments S2–S4, which mediate contractions of the
periurethral and pelvic floor muscles resulting in a pulsatile projectile ejaculation.
amplitude and frequency were shown to be more effec-
tive, with the best results achieved at an amplitude of
2.5 mm and frequency of 100 Hz.31 The underlying prin-
ciple is that supraphysiological stimulation of the dorsal
penile nerve through mechanical vibration can activate
an a­natomically intact but dormant ejaculatory reflex.
Procedure and mechanisms
PVS is performed using a medical vibrator, which stim-
ulates the dorsal and/or the ventral side of the glans
penis through a vibrating disc. We recommend a treat-
ment algorithm that involves stimulation for repeated
periods of 2 min, punctuated by rest intervals of around
30 s, until ejaculation occurs. This algorithm is based
on the observation that PVS usually induces ejaculation
within 2 min—a study of 211 men with SCI showed that
the mean time from onset of stimulation to ejaculation
was 1.72 ± 0.15 min, and that 89% of men who achieved
ejacu­l ation with high amplitude stimulation did so
within 2 min.32 The intervals are needed because longer
periods of stimulation can cause damage to the sensi-
tive skin on the glans penis; clinical experience shows
that the risk of abrasions is especially high, as many
men with SCI have abolished or reduced sensation of
the glans. When PVS is successful, it generally activates
both the sympathetic and somatic arms of the ejacula-
tory reflex, resulting, therefore, in projectile antegrade
ejaculation.29,30 Once the projectile ejaculatory phase
commences, the PVS device is removed and the ejaculate
is collected. To maximize the sperm yield, the urethra is
subsequently manually milked for residual fluid, which
is also collected.
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REVIEWS
No absolute upper limit exists for the number of
stimulation periods that can be carried out within one
PVS attempt, but the skin should be inspected during
stimulation breaks and, at the very latest, the procedure
should be terminated if lesions begin to form. Although
no specific research exists on the matter, it seems reason-
able to make at least one more PVS attempt after the skin
has healed, since the largest case series show that more
than one PVS attempt can be required to induce ejacula-
tion.18,32 Importantly, the success rate can be increased
with the use of additional stimulation in such cases. Thus,
simultaneous use of two vibrators, one on the dorsal and
one on the ventral surface of the glans, was shown to
produce ejaculation in ~20% of PVS nonresponders in
a retrospective analysis of 297 men with SCI.33 In addi-
tion, accessory abdominal electrical stimulation with an
over-the-counter abdominal muscle stimulator with
simultaneous PVS was able to cause ejaculation in two
initial nonresponders, as reported by Kafetsoulis and co-
workers.34 The success rate might be further increased
with concurrent use of oral phosphodiesterase‑5 (PDE‑5)
inhibitors as a study from 2008 (n = 418) showed that men
with SCI who were randomized to vardenafil had greater
ejaculatory success with normal sexual stimulation com-
pared to those who received placebo (19% versus 10%,
P <0.001).35 The assumed mechanism is that improved
erections increase exposure of the penile sensory nerve
endings, thereby amplifying the nerve signals induced
by PVS. Meanwhile, conflicting evidence exists regard-
ing an additional effect of the sympathomimetic agent,
midodrine, as one case series has shown that addi-
tion of the drug salvaged 22% of PVS nonresponders,
whereas a subsequent randomized trial in 20 men with
SCI failed to confirm this finding.36,37 Further study of
PVS and drug combinations are needed before specific
r­ecommendations can be made.
Both the afferent and efferent limbs of the reflex must
be intact in order for PVS to induce ejaculation. This
requirement is reflected in the PVS success rates observed
when comparing men with damage to different levels of
the spinal cord. A success rate of almost 90% has been
achieved in men with an injury above the reflex centre
at T10, because the sympathetic nerve fibres crucial for
ejaculation are still present in these patients. By compari-
son, the success rate drops dramatically to only 15–20%
in men with injuries below this level.6,38 The importance
of the afferent limb of the reflex has been e­legantly dem-
onstrated in a study of eight men with SCI in whom
an initial PVS response was completely a­b olished by
a­naesthetic block of the dorsal penile nerves.39
Adverse effects of PVS
The adverse effects associated with PVS are mild and
usually only include skin irritation or minor local
lesions, which do not require medical intervention.
However, care must be taken when performing PVS
in men with penile implants, as the vibrator can push
the glans onto the cylinder tips resulting in trauma and
erosion. The clinician must also be aware that any kind
of sexual stimulation, as well as the ejaculatory response
REVIEWS
Sympathomimetic agents (optional)
Can be effective in mild neurological disorders
Treatment is administered in conjuction with
sexual intercourse around the time of ovulation only
Penile vibratory stimulation
Cheap and with limited adverse effects
Can be performed by patients in their own home
with subsequent self-insemination
Effective in up to 90% of spinal-cord-injured men
with lesions above T10 and in 15–20% of men
with injuries below this level
Limited clinical experience in non-SCI neurogenic anejaculation
Electroejaculation
Universally effective in neurogenic anejaculation
Requires general anaesthesia in men
with retained pelvic sensation
Can be combined with all assisted reproductive techniques
Percutaneous sperm aspiration
Sperm can be aspirated from the vas deferens,
the epididymis or the testes
Adverse effects include transient pain, bleeding and infection
Commits the couple to in vitro fertilization with or
without intracytoplasmic sperm injection
Testicular biopsy
The most invasive and expensive method of sperm retrieval
Can be performed percutaneously with a large-gauge
needle/biopsy gun or via surgical exploration
Can cause severe adverse effects in rare cases
Commits the couple to in vitro fertilization
Figure 2 | A stepwise algorithm for treating neurogenic
Nature Reviews | Urology
anejaculation. When treating neurogenic anejaculation
the goal is to obtain viable sperm cells to be used for
reproduction. Methods for sperm collection should be
considered and employed in a step-wise fashion starting
with the most cost-effective and least invasive options.
itself, can be associated with a significant rise in systolic
blood pressure in men with SCI, owing to an unwanted
sympathetic reflex response.36 Thus, common practi-
cal precautions include serial blood pressure measure-
ments, while PVS may be withheld or used with the
utmost caution in patients with severe cardiac disease or
untreated hypertension. Penile stimulation (both using
PVS and through normal sexual activity) can also induce
a severe and uninhibited sympathetic reflex response
called autonomic dysreflexia in men with an injury at
or above spinal level T6.40 Patients who are at risk of
autonomic dysreflexia have often experienced prior epi-
sodes of headache and flushing as a result of rising blood
pressure in response to stimuli below the level of their
injury. If similar symptoms arise during PVS or if the
patient’s blood pressure rises dramatically, stimulation
should be stopped immediately and the patient should
be returned to an upright position, as such symptoms
can signal the beginning of pronounced acute hyper-
tension, which, in rare cases, results in stroke, seizure,
and can cause death.41 To reduce the risk of autonomic
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dysreflexia, at-risk patients can be pretreated with
10–40 mg of sublingual nifedipine approximately 15 min
prior to PVS, which can blunt the increase in blood pres-
sure.42–44 However, presymptoms can be limited in men
with complete spinal injuries and the treating clinician
should be especially wary of changes in blood pressure
in these patients.40
PVS success in men with neurogenic anejaculation of a
non-SCI aetiology has been reported but the data are very
limited.45 However, based on the mechanism of action,
it can be speculated that the method could be effective
in anyone with an intact ejaculatory reflex arc, and—
as autonomic dysreflexia is not a concern in patients
without SCI—the method can be safely attempted. In
these men, it should be noted that cortical inhibition is
often especially pronounced in the clinic manifesting as a
lack of ejaculation response. Thus, it might be beneficial
to allow such patients to take the device home in order to
perform the procedure in a more comfortable setting.
PVS devices
Two commercially available devices for PVS are cur-
rently in use. The most thoroughly studied is the
FertiCare® vibrator (Multicept A/S, Frederiksberg,
Denmark) (Figure 3).18,32–34 This device has adjustable
settings for both amplitude and frequency, and stimu-
lates one side of the glans at a time. A second device,
Viberect®‑X3 (Reflexonic, Frederick, MD, USA) was
approved by the FDA in 2011 (Figure 4). In contrast to
the FertiCare®, this device is set to a nonadjustable ampli-
tude of 4 mm and a frequency of 70–100 Hz and it deliver­s
simultaneous stimulation of the dorsal and ventral
sides of the glans.45 Currently, the only data regarding
the use of the Viberect®‑X3 device comes from a small
study of 30 men with injuries above spinal level T10, in
whom an ejaculatory success rate of 77% was observed.45
This study did not compare the effect with that of the
FertiCare® and further study is needed to assess potential
differences between the devices.
Electroejaculation
The use of electroejaculation (EEJ) in men with SCI was
originally adopted from veterinary medicine, but the
method has proved universally useful in over­coming
neurogenic anejaculation. EEJ does not rely completely
on an intact ejaculatory reflex, as an electrical current
is used to directly stimulate the smooth muscu­lature
in the seminal ductal system and the accessory sex
glands in order to induce seminal emission. To a lesser
extent, the method also activates the perineal and peri-
urethral muscles, which enables some degree of ante-
grade ejaculation.46 However, the coordinated pulsatile
phase of ejaculation is not induced to the same degree
as in PVS and ejaculation often happens in a non-­
projectile, dribbling fashion with at least some degree of
retrograde ejaculation.
Mechanisms and procedure
Prior to EEJ, rectoscopy must be performed to rule
out pre-existing rectal mucosal lesions, which are a
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 REVIEWS

contraindication for the procedure, which requires use of

a rectal probe In addition, bladder emptying and instal-
lation of a sperm-friendly medium by catheterization is
recommended, as the tendency for retrograde ejaculation
with EEJ might result in a need for postejaculation sperm
harvest from the bladder.17,47
The electrical current is delivered through the rectal
probe, which is inserted with the patient placed in the
lateral decubitus position with the electrodes facing
the seminal vesicles and the prostate. In men with abol-
ished sensation in the pelvic area, EEJ can be performed
without sedation. However, patients with other neuro-
logical conditions (such as multiple sclerosis or diabe-
tes) or those who retain some pelvic sensation require
general anaesthesia as the procedure is otherwise very
painful.48,49 With the probe in place, an electrical current
is delivered in waves with 5 s of stimulation, which is
stopped abruptly and followed by a 20 s pause, during
which time ejaculation occurs. The first stimulation is
performed at 2.5–5 V and the voltage is then increased
by 1–5 V for each subsequent wave, until a maximum of
up to 30 V is reached. The actual ejaculatory response
develops during the periods of electrical silence, during
which the ejaculate is collected. The pattern is repeated
until no more ejaculate is produced. As with PVS, the
urethra must be manually milked in order to retrieve as
much semen as possible. Following the EEJ procedure,
any retrograde fraction of the ejaculate is then collected
by bladder catheterization, and the sperm are processed
for use in ART.50–52 Finally, rectoscopy must be repeated
in order to ensure that the probe has not caused any
mucosal lesions.
Success rates of EEJ
The overall success rate of EEJ is very high in general—
the largest series of EEJ published to date showed a 94.1%
success rate in SCI men (897/953 EEJ procedures per-
formed in 210 men induced ejaculation). Overall, a total
of 193 men (91.9%) of men in this study achieved at least
one ejaculation.18 Importantly, all of the 17 patients who
did not ejaculate with the treatment felt pain during the
first EEJ attempt and refused further trials under anaes-
thesia. The rate of antegrade ejaculation in the successful
procedures is not made clear in the study, but the ante-
grade fraction of the ejaculate is known to be increased
by the abrupt discontinuation of electrical stimulation.
Thus, a small trial in which recording of external and
internal sphincter pressures was performed in men
with SCI during EEJ showed that forceful contraction
of the external sphincter followed by contraction of the
internal sphincter always preceded ejaculation and that
termination of the electrical stimulation during ejacu-
lation enabled a greater level of external sphincter
relaxation, decreasing the retrograde fraction of the
ejaculate.44 The clinical relevance of this original study
has subsequently been confirmed in a further trial of
12 men with SCI, in whom interrupted current deliv-
ery resulted in an increased antegrade volume, as well
as more sperm in the antegrade fraction compared with
continuous delivery. However, the retrograde fraction
Figure 3 | The FertiCare®vibrator (Multicept A/S,
Denmark). The device activates theNature Reviews
ejaculatory | Urology
reflex
by penile vibration. With an amplitude of 2.5 mm and a
frequency of 100 Hz, it can induce ejaculation in the
majority of men with SCI.
was higher for continuous delivery, meaning that the
total number of sperm as well as motile sperm recov-
ered for ART were similar between the two methods.48
As with PVS, the data in men with neurogenic anejacu-
lation of a non-SCI aetiology are scarce; however, the
method has been used successfully in small series of
men with several other causes of neurogenic anejacu-
lation including multiple sclerosis, myelomeningocele
and anejaculation associated with nerve damage during
retroperitoneal lymph node dissection.53–55
Advantages and disadvantages of EEJ
EEJ is generally safe and the only absolute contraindica-
tions include preexisting rectal lesions or inflammation
and bleeding disorders. In addition, anticoagulation
therapy should be paused before EEJ, based on individ­
ual evaluation, and restarted immediately after the pro-
cedure. The EEJ-induced ejaculatory response can also
cause autonomic dysreflexia. As patients undergoing
EEJ either have abolished pelvic sensation or are under
general anaesthesia, it is, therefore, prudent to pretreat
all men with an injury at or above spinal level T6 with
10–40 mg of sublingual nifedipine prior to EEJ, and
blood pressure monitoring during the procedure is an
absolute requirement.
In spite of its advantages in terms of success rates
compared with PVS, EEJ is more demanding to both
the patient and clinical staff and more expensive than
Figure 4 | The Viberect®‑X3 (Reflexonic, USA).
Nature This |device
Reviews Urology
delivers stimulation to both the dorsal and ventral sides of
the glans penis. When set to an amplitude of 4 mm and a
frequency of 70–100 Hz, it can achieve ejaculatory results
similar to that of the FertiCare®in men with SCI. However,
further studies are awaited.

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REVIEWS
Figure 5 | The Seager Model 14 Electroejaculator
Nature Reviews (Dalzell
| Urology
Medical Systems, USA). This device induces ejaculation
using an electric current delivered via a rectal probe. The
ejaculatory success rate is close to 100% in patients who
can accept the treatment. However, it requires general
anaesthesia in men with preserved pelvic sensation.
PVS at an approximate price of $25,000 USD per patient.
In addition, EEJ has been shown to result in a lower
sperm quality—in a small study of 11 men with SCI who
received both EEJ and PVS in random order, specimens
collected using PVS had greater sperm motility (26.0%
after PVS versus 10.7% after EEJ), viability (25.2%
versus 9.7%) and motile sperm count (185.0 × 106 versus
97.0 × 106).56 Unsurprisingly, EEJ is also less popular with
patients than PVS.56
EEJ Devices
The only device currently marketed for EEJ is the Seager
Model 14 Electroejaculator (Dalzell Medical Systems,
USA) (Figure 5). The meters on the machine itself
display the voltage and the current being delivered as
well as the stimulation count and time. Through an
inbuilt thermometer in the rectal probe, the machine also
shows the rectal temperature and the stimulation is auto-
matically terminated if this reaches the recommended
maximum of 39.5 °C in order to avoid mucosal damage.
Outcomes of assisted ejaculation
SCI has long been known to cause deterioration of sperm
motility and viability, with the most severe effect in men
with complete spinal lesions.57,58 Elevated scrotal tem-
perature, reduced frequency of ejaculations, recurrent
urinary tract infections, and endocrine disturbances
have all been proposed as mechanisms by which these
abnormalities arise, but all of these factors have since
been rejected as adequate explanations. 59–64 Instead,
it is thought inappropriate activation of the immune
system65–70 and factors in sperm storage and transporta-
tion and in the seminal plasma71–73 are the likely causes.
In this context, the influence of the seminal plasma is
particularly interesting, as sperm aspirated from the
vas deferens seem to have higher motility than those
h­arvested from the ejaculate in men with SCI.73,74
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© 2015 Macmillan Publishers Limited. All rights reserved
In spite of the potential for poor sperm quality, viable
and motile sperm cells can be obtained through mastur-
bation or assisted ejaculation in the vast majority of men
with SCI. A trial of 500 such men showed that 9% were
able to ejaculate through masturbation. Of the remain-
ing 461 men, an 54% responded to PVS regardless of
their site of injury and, of the 210 nonresponders who
proceeded to EEJ, all patients who underwent the entire
EEJ procedure achieved ejaculation. These results are
equivalent to an overall success rate of 97%.18 Moreover,
sperm were present in 91% of all ejaculates in the study
and in 62.8% of cases the total motile sperm count was
>5 million, enabling use of the least invasive types of
ART—i­ntravaginal insemination (IVI) and intra­uterine
insemination (IUI). Another study investigating the
same patient population confirmed that the majority of
men with SCI had normal sperm concentrations in their
induced ejaculates and further reported that even in those
who exhibited azoospermia after PVS or EEJ, up to one-
third of patients had viable sperm present in ejaculates
obtained from s­ubsequent EEJ procedures.75
A limited body of data suggests that semen quality is
reduced in both patients with diabetes and those with
multiple sclerosis.76–81 Proposed mechanisms for this
reduction include endocrine disturbances and damage to
the developing sperm from chronic inflammatory pro-
cesses.82 However, the link between these diseases and
infertility is still controversial and most patients have
semen parameters within the normal range.
Surgical sperm retrieval
In men in whom an ejaculate cannot be obtained, or when
no viable sperm are present, more invasive measures must
be used. These entail sperm retrieval directly from the
epididymis, vas deferens, or testis, either by percutane-
ous aspiration or biopsy, or by surgical exploration. The
relatively low sperm yield from such procedures gener-
ally necessitates the use of the most complicated ART
procedures, namely in vitro fertilization (IVF) with or
without intracytoplasmic sperm injection (ICSI). Like
the methods for assisted ejaculation, surgical sperm
retrieval methods should be considered in a stepwise
fashion with the least invasive method expected to
produce an acceptable sperm yield attempted first. In this
regard, one must keep in mind that men who are infer-
tile owing to neurogenic anejaculation most often have
preserved testicular sperm production. Common adverse
effects of surgical sperm retrieval include minor haemato-
mas and transient pain. The procedures also carry a small
risk of infection, severe bleeding and prolonged pain.
Vasal and epididymal sperm retrieval
The least invasive method of direct sperm retrieval is
by percutaneous aspiration from the vas deferens or the
epididymis through a small needle, under local anaes-
thesia. Percutaneous aspiration typically produces a
yield of >2 million sperm when performed in men with
normal sperm production.83 The collection procedures
can also be performed through a small scrotal incision,
whereby the vas or the epididymis is incised using a
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loupe or microscope to improve visualization and guide
the procedure.84 Adverse effects associated with percu-
taneous aspiration from the vas or epididymis are minor
and include transient pain, bleeding or infection in ~1%
of patients.83
Testicular sperm retrieval
Testicular sperm retrieval can be performed by aspira-
tion, biopsy, or surgical exploration. The yield is generally
lower than with more distal aspiration.85 Testicular sperm
aspiration is performed under local anaesthesia with
insertion of a fine needle into the testicular parenchyma
through the scrotal skin.86 The risk of complications is
equivalent to that seen in vasal or epididymal aspiration
and clinically relevant intratesticular h­aematomas are
very rare.83
In percutaneous testicular biopsy, a large gauge needle
or biopsy gun is used to obtain small testicular biopsy
samples, which are subsequently harvested for sperm
cells. This technique provides a better sperm yield than
fine needle aspiration but is also associated with more
severe adverse effects, with hematomas noted in up to
5% of patients.86 The next step in invasiveness is biopsy
through surgical exploration. It should be considered
carefully if this approach is necessary to obtain sperm
as it is associated with higher costs and more adverse
effects than both aspiration and percutaneous biopsies.83
In extremely rare cases testicular biopsies have been
resulted in loss of a testicle as reported by Dieckmann
et al.87 in a prospective evaluation of biopsy c­omplications
in 1,874 patients.
To carry out testicular biopsy, an incision is made
through the skin and the fascia are opened. A small
cut is then made in the tunica albuginea and a biopsy
is obtained most often using surgical scissors. The tech-
nique has been refined with the use of an operating
microscope to specifically identify seminiferous tubules
containing sperm cells and thereby improve the yield.
This method is particularly useful in patients with limited
sperm production.88
Assisted reproductive techniques
Sperm collected using assisted ejaculation or direct
retrieval can be used for IVI or ART in the form of IUI
or IVF/ICSI.
In IVI, the ejaculate is injected into the vagina with a
needleless syringe around the time of ovulation.29 This
procedure can be done in the clinic or by the couple
themselves as so-called self-insemination following PVS.
Before any home attempts are made, autonomic dys­
reflexia must be excluded by performing a monitored
PVS trial in the clinic.
In IUI, the fraction of motile sperm is isolated and
injected into the uterine cavity.89 Hereby, the cervix is
bypassed and a greater proportion of sperm reach the
fallo­pian tubes.90 IUI can be combined with ovarian
stimu­lation using antioestrogens or gonadotropins in
order to increase the number of mature oocytes and
maximize the chances of fertilization.91 However, this
additional treatment is usually unnecessary in pure male
NATURE REVIEWS | UROLOGY ADVANCE ONLINE PUBLICATION  |  7
© 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS
factor infertility,92,93 and can result in ovarian hyperstimu-
lation syndrome. Ovarian stimulation also increases the
risk of multiple pregnancies, which is associated with
peri­natal and maternal morbidity and perinatal mortal-
ity.94–98 Thus, this treatment should only be considered if
there is also a female component to the couple’s infertility.
In IVF, oocytes and sperm are mixed in Petri dishes
in order for fertilization to occur. ICSI entails inject-
ing sperm directly into oocytes in order to facilitate the
process. The oocytes are extracted transvaginally after
ovarian stimulation. After about 5 days of in vitro develop­
ment, one or more embryos are injected into the uterus
for implantation.99 With IVF, fertilization can be achieved
with low numbers of functioning sperm, whereas ICSI
theoretically enables fertilization even in situations
whereby only a single non-motile sperm is available.100–102
Choice of ART procedure
The ART method of choice depends somewhat on patient
characteristics and preferences but in patients with iso-
lated male factor infertility, the main determinant is the
total motile sperm count of the obtained semen sample.
In patients with at least 4–5 million motile sperm in the
sample, the simple and low-cost methods of IVI and IUI
(costing around $200–$600 per procedure) are generally
feasible.103,104 This level of motile sperm can only be recov-
ered using assisted ejaculation or sperm aspiration and, as
EEJ requires a treating physician and sometimes anaes-
thesia, self-insemination can only be carried out follow­
ing PVS. After surgical sperm retrieval or in patients in
whom more modest sperm yields have been collected
with assisted ejaculation or aspiration, the more invasive
and expensive techniques of IVF with or without ICSI are
necessary to achieve pregnancy.
In most neurological diseases, no specific studies on
success rates of insemination procedures exist; however,
this is not the case in men with SCI, and many studies
exist in these patients. The reported pregnancy rate after
IVI in partners of men with SCI varies, but overall has
been reported to be 25–70% per couple.48,105–111 In the
largest study of self-insemination to date, 60 of 140 part-
ners of men with SCI achieved 82 pregnancies resulting
in the delivery of 73 healthy babies with a median time to
first pregnancy of 22.8 months.112 By comparison, IUI is
reported to result in pregnancies in ~30% of couples with
a male partner with SCI.104,105,107,109,110 The total motile
sperm count is the most important predictive factor for
success with the method. Both Ohl et al.104 and Kathiresan
et al.110 have reported that pregnancies are rare following
attempts with total motile sperm counts below 4 million.
Case series investigating IVF and ICSI in couples with a
male partner with SCI have reported successful pregnan-
cies for between 38% and 100% of couples.106–110,112,114–117
However, although IVF and ICSI are good options, it is
important take the cost of the procedures into account
($8,000–$12,000 per cycle), and to remember the added
maternal risks from ovarian hyperstimulation and
oocyte retrieval. In addition, the procedures include a
risk of multiple gestation pregnancy, and increased rate
of p­regnancy loss.97
REVIEWS

Conclusions Review criteria

Neurological disorders can result in anejaculation owing
to disruption of the ejaculatory reflex arc. This mech­
anism is most often the case in patients with SCI. Men
with SCI are usually young and many are interested in
starting a family. In the vast majority of these patients,
motile sperm can be obtained through assisted ejacula-
tion. With high motile sperm counts, this enables the use
of inexpensive and noninvasive methods of insemina-
tion. Invasive techniques for sperm retrieval and compli-
cated and expensive ART procedures should be reserved
for patients in which the simpler methods have failed.
Although the literature is scarce on non-SCI neurogenic
anejaculation, it is reasonable to conclude that the same
stepwise sperm retrieval algorithm should be applied in
these patients.
To identify articles describing neurogenic anejaculation
and its treatment, we conducted a search of Medline and
the Cochrane Library using the terms (“Ejaculation” OR
“Fertility”) AND (“neurogenic” OR “Spinal Cord Injuries” OR
“Paraplegia” OR “Quadriplegia” OR “Diabetes Mellitus”
OR “Multiple Sclerosis” OR “Neural Tube Defects”). We
restricted our search to full-text English-language papers
in male subjects published between January 1970 and
March 2015. We included articles regarding both animal
studies and humans. Articles were screened based on
titles and abstracts while relevant articles were selected
based on a full review. Reference lists for selected articles
were manually searched for further leads. Background
literature regarding normal ejaculatory function and as well
as surgical sperm retrieval and ART in the general infertile
population were added at the authors’ discretion.

1. Fode, M. et al. Male sexual dysfunction and
infertility associated with neurological disorders.
Asian J. Androl. 14,61–68 (2012).
2. O’Connor, P. Incidence and patterns of spinal
cord injury in Australia. Accid. Anal. Prev. 34,
405–415 (2002).
3. Rathore, M. F., Hanif, S., Farooq, F., Ahmad, N.
& Mansoor, S. N. Traumatic spinal cord injuries
at a tertiary care rehabilitation institute in
Pakistan. J. Pak. Med. Assoc. 58, 53–57 (2008).
4. Kuptniratsaikul, V. Epidemiology of spinal cord
injuries: a study in the Spinal Unit, Siriraj
Hospital, Thailand, 1997–2000. J. Med. Assoc.
Thai. 86, 1116–1121 (2003).
5. Exner, G. & Meinecke, F. W. Trends in the
treatment of patients with spinal cord lesions
seen within a period of 20 years in German
centers. Spinal Cord 35, 415–419 (1997).
6. Kafetsoulis, A., Brackett, N. L., Ibrahim, E.,
Attia, G. R. & Lynne, C. M. Current trends in the
treatment of infertility in men with spinal cord
injury. Fertil. Steril. 86, 781–789 (2006).
7. Giuliano, F. & Clement, P. Neuroanatomy and
physiology of ejaculation. Annu. Rev. Sex Res. 16,
190–216 (2005).
8. Coolen, L. M., Allard, J., Truitt, W. A. &
McKenna, K. E. Central regulation of ejaculation.
Physiol Behav. 83, 203–215 (2004).
9. Thomas, A. J. Jr. Ejaculatory dysfunction.
Fertil. Steril. 39, 445–454 (1983).
10. Turek, P. J. Male Reproductive Physiology in
Campbell Walsh Urology Vol. 1 (eds Wein, A. J.,
Kavoussi, L. R., Novick, A., Partin, A. &
Peters, C.) 591–615 (Elsevier Saunders, 2012).
11. Bohlen, D., Hugonnet, C. L., Mills, R. D.,
Weise, E. S. & Schmid, H. P. Five meters of
H(2)O: the pressure at the urinary bladder neck
during human ejaculation. Prostate 44, 339–341
(2000).
12. Colpi, G. et al. EAU guidelines on ejaculatory
dysfunction. Eur. Urol. 46, 555–558 (2004).
13. Yavetz, H. et al. Retrograde ejaculation.
Hum. Reprod. 9, 381–386 (1994).
14. Ohl, D. A., Quallich, S. A., Sonksen, J.,
Brackett, N. L. & Lynne, C. M. Anejaculation
and retrograde ejaculation. Urol. Clin. North Am.
35, 211–220 (2008).
15. Kamischke, A. & Nieschlag, E. Update on
medical treatment of ejaculatory disorders.
Int. J. Androl. 25, 333–344 (2002).
16. Gilja, I., Parazajder, J., Radej, M., Cvitkovic, P.
& Kovacic, M. Retrograde ejaculation and loss
of emission: possibilities of conservative
treatment. Eur. Urol. 25, 226–228 (1994).
17. Crich, J. P. & Jequier, A. M. Infertility in men
with retrograde ejaculation: the action of urine
on sperm motility, and a simple method for
achieving antegrade ejaculation. Fertil. Steril. 30,
572–576 (1978).
18. Brackett, N. L., Ibrahim, E., Iremashvili, V.,
Aballa, T. C. & Lynne, C. M. Treatment for
ejaculatory dysfunction in men with spinal cord
injury: an 18-year single center experience.
J. Urol. 183, 2304–2308 (2010).
19. Decter, R. M. et al. Reproductive understanding,
sexual functioning and testosterone levels in
men with spina bifida. J. Urol. 157, 1466–1468
(1997).
20. Frohman, E. M. & Wingerchuk, D. M. Clinical
practice. Transverse myelitis. N. Engl. J. Med.
363, 564–572 (2010).
21. Haensch, C. A. & Jorg, J. Autonomic dysfunction
in multiple sclerosis. J. Neurol. 253 (Suppl. 1),
I3–I9 (2006).
22. Weinstein, M. H. & Machleder, H. I. Sexual
function after aorto-lliac surgery. Ann. Surg. 181,
787–790 (1975).
23. Kedia, K. R., Markland, C. & Fraley, E. E.
Sexual function after high retroperitoneal
lymphadenectomy. Urol. Clin. North Am. 4,
523–528 (1977).
24. Pearce, S., Steinberg, Z. & Eggener, S. Critical
evaluation of modified templates and current
trends in retroperitoneal lymph node dissection.
Curr. Urol. Rep. 14, 511–517 (2013).
25. Genuth, S. Insights from the diabetes control
and complications trial/epidemiology of
diabetes interventions and complications study
on the use of intensive glycemic treatment
to reduce the risk of complications of type 1
diabetes. Endocr. Pract. 12 (Suppl. 1), 34–41
(2006).
26. Dunsmuir, W. D. & Holmes, S. A. The aetiology
and management of erectile, ejaculatory, and
fertility problems in men with diabetes mellitus.
Diabet. Med. 13, 700–708 (1996).
27. Sexton, W. J. & Jarow, J. P. Effect of diabetes
mellitus upon male reproductive function.
Urology 49, 508–513 (1997).
28. Brindley, G. S. Reflex ejaculation under vibratory
stimulation in paraplegic men. Paraplegia 19,
299–302 (1981).
29. Brackett, N. L. Semen retrieval by penile
vibratory stimulation in men with spinal cord
injury. Hum. Reprod. Update 5, 216–222
(1999).
30. Sonksen, J. & Ohl, D. A. Penile vibratory
stimulation and electroejaculation in the
treatment of ejaculatory dysfunction.
Int. J. Androl. 25, 324–332 (2002).
31. Sonksen, J., Biering-Sorensen, F.
& Kristensen, J. K. Ejaculation induced by penile
vibratory stimulation in men with spinal cord
injuries. The importance of the vibratory
amplitude. Paraplegia 32, 651–660 (1994).
32. Brackett, N. L. et al. An analysis of 653 trials
of penile vibratory stimulation in men with spinal
cord injury. J. Urol. 159, 1931–1934 (1998).
33. Brackett, N. L., Kafetsoulis, A., Ibrahim, E.,
Aballa, T. C. & Lynne, C. M. Application of
2 vibrators salvages ejaculatory failures to
1 vibrator during penile vibratory stimulation
in men with spinal cord injuries. J. Urol. 177,
660–663 (2007).
34. Kafetsoulis, A. et al. Abdominal electrical
stimulation rescues failures to penile vibratory
stimulation in men with spinal cord injury:
a report of two cases. Urology 68, 204–211
(2006).
35. Giuliano, F. et al. Vardenafil improves ejaculation
success rates and self-confidence in men with
erectile dysfunction due to spinal cord injury.
Spine (Phila Pa 1976) 33, 709–715 (2008).
36. Courtois, F. J. et al. Blood pressure changes
during sexual stimulation, ejaculation and
midodrine treatment in men with spinal cord
injury. BJU Int. 101, 331–337 (2008).
37. Leduc, B. E. et al. Midodrine in patients with
spinal cord injury and anejaculation: A double-
blind randomized placebo-controlled pilot study.
J. Spinal Cord Med. 38, 57–62 (2015).
38. Sonksen, J. Assisted ejaculation and semen
characteristics in spinal cord injured males.
Scand. J. Urol. Nephrol. Suppl. 2003, 1–31 (2003).
39. Wieder, J. A., Brackett, N. L., Lynne, C. M.,
Green, J. T. & Aballa, T. C. Anesthetic block of
the dorsal penile nerve inhibits vibratory-induced
ejaculation in men with spinal cord injuries.
Urology 55, 915–917 (2000).
40. Ekland, M. B., Krassioukov, A. V., McBride, K. E.
& Elliott, S. L. Incidence of autonomic dysreflexia
and silent autonomic dysreflexia in men with
spinal cord injury undergoing sperm retrieval:
implications for clinical practice. J. Spinal Cord.
Med. 31, 33–39 (2008).
41. Wan, D. & Krassioukov, A. V. Life-threatening
outcomes associated with autonomic
dysreflexia: a clinical review. J. Spinal Cord. Med.
37, 2–10 (2014).
42. Elliott, S. & Krassioukov, A. Malignant autonomic
dysreflexia in spinal cord injured men.
Spinal Cord 44, 386–392 (2006).

8  |  ADVANCE ONLINE PUBLICATION www.nature.com/nrurol

© 2015 Macmillan Publishers Limited. All rights reserved

43. Sheel, A. W., Krassioukov, A. V., Inglis, J. T.
& Elliott, S. L. Autonomic dysreflexia during
sperm retrieval in spinal cord injury: influence of
lesion level and sildenafil citrate. J. Appl. Physiol.
99, 53–58 (2005).
44. Steinberger, R. E., Ohl, D. A., Bennett, C. J.,
McCabe, M. & Wang, S. C. Nifedipine
pretreatment for autonomic dysreflexia during
electroejaculation. Urology 36, 228–231 (1990).
45. Castle, S. M. et al. Safety and efficacy of a new
device for inducing ejaculation in men with
spinal cord injuries. Spinal Cord 52 (Suppl. 2),
S27–S29 (2014).
46. Sonksen, J., Ohl, D. A. & Wedemeyer, G.
Sphincteric events during penile vibratory
ejaculation and electroejaculation in men
with spinal cord injuries. J. Urol. 165, 426–429
(2001).
47. Suominen, J. J., Kilkku, P. P., Taina, E. J. &
Puntala, P. V. Successful treatment of infertility
due to retrograde ejaculation by instillation of
serum-containing medium into the bladder.
A case report. Int. J. Androl. 14, 87–90 (1991).
48. Perkash, I., Martin, D. E., Warner, H.,
Blank, M. S. & Collins, D. C. Reproductive
biology of paraplegics: results of semen
collection, testicular biopsy and serum hormone
evaluation. J. Urol. 134, 284–288 (1985).
49. Sarkarati, M., Rossier, A. B. & Fam, B. A.
Experience in vibratory and electro-ejaculation
techniques in spinal cord injury patients:
a preliminary report. J. Urol. 138, 59–62 (1987).
50. Braude, P. R., Ross, L. D., Bolton, V. N.
& Ockenden, K. Retrograde ejaculation:
a systematic approach to non-invasive recovery
of spermatozoa from post-ejaculatory urine for
artificial insemination. Br. J. Obstet. Gynaecol.
94, 76–83 (1987).
51. Shangold, G. A., Cantor, B. & Schreiber, J. R.
Treatment of infertility due to retrograde
ejaculation: a simple, cost-effective method.
Fertil. Steril. 54, 175–177 (1990).
52. Okada, H., Goda, K., Koshida, M. &
Kamidono, S. Pregnancy by insemination of
cryopreserved spermatozoa from a man with
retrograde ejaculation: a case report. J. Reprod.
Med. 49, 389–391 (2004).
53. Hsiao, W., Deveci, S. & Mulhall, J. P. Outcomes
of the management of post-chemotherapy
retroperitoneal lymph node dissection-associated
anejaculation. BJU Int. 110, 1196–1200 (2012).
54. Kathiresan, A. S. et al. Anejaculatory infertility
due to multiple sclerosis. Andrologia
44 (Suppl. 1), 833–835 (2012).
55. Hultling, C., Levi, R., Amark, S. P. & Sjoblom, P.
Semen retrieval and analysis in men with
myelomeningocele. Dev. Med. Child Neurol. 42,
681–684 (2000).
56. Ohl, D. A., Sonksen, J., Menge, A. C.,
McCabe, M. & Keller, L. M. Electroejaculation
versus vibratory stimulation in spinal cord
injured men: sperm quality and patient
preference. J. Urol. 157, 2147–2149 (1997).
57. Iremashvili, V. V., Brackett, N. L., Ibrahim, E.,
Aballa, T. C. & Lynne, C. M. A minority of men
with spinal cord injury have normal semen
qualitycan we learn from them? A case-control
study. Urology 76, 347–351 (2010).
58. Denil, J., Ohl, D. A., Menge, A. C., Keller, L. M.
& McCabe, M. Functional characteristics of
sperm obtained by electroejaculation. J. Urol.
147, 69–72 (1992).
59. Siosteen, A., Forssman, L., Steen, Y., Sullivan, L.
& Wickstrom, I. Quality of semen after repeated
ejaculation treatment in spinal cord injury men.
Paraplegia 28, 96–104 (1990).
60. Hamid, R., Patki, P., Bywater, H., Shah, P. J.
& Craggs, M. D. Effects of repeated ejaculations
NATURE REVIEWS | UROLOGY ADVANCE ONLINE PUBLICATION  |  9
on semen characteristics following spinal cord
injury. Spinal Cord 44, 369–373 (2006).
61. Das, S. et al. Does repeated electro-ejaculation
improve sperm quality in spinal cord injured
men? Spinal Cord 44, 753–756 (2006).
62. Brackett, N. L., Lynne, C. M., Weizman, M. S.,
Bloch, W. E. & Padron, O. F. Scrotal and oral
temperatures are not related to semen quality of
serum gonadotropin levels in spinal cord-injured
men. J. Androl. 15, 614–619 (1994).
63. Ohl, D. A. et al. Fertility of spinal cord injured
males: effect of genitourinary infection
and bladder management on results of
electroejaculation. J. Am. Paraplegia Soc. 15,
53–59 (1992).
64. Brackett, N. L., Lynne, C. M., Weizman, M. S.,
Bloch, W. E. & Abae, M. Endocrine profiles and
semen quality of spinal cord injured men. J. Urol.
151, 114–119 (1994).
65. Basu, S. et al. Cytofluorographic identification
of activated T‑cell subpopulations in the semen
of men with spinal cord injuries. J. Androl. 23,
551–556 (2002).
66. Aird, I. A., Vince, G. S., Bates, M. D.,
Johnson, P. M. & Lewis-Jones, I. D. Leukocytes
in semen from men with spinal cord injuries.
Fertil. Steril. 72, 97–103 (1999).
67. Trabulsi, E. J., Shupp-Byrne, D., Sedor, J.
& Hirsch, I. H. Leukocyte subtypes in
electroejaculates of spinal cord injured men.
Arch. Phys. Med. Rehabil. 83, 31–34 (2002).
68. Basu, S., Aballa, T. C., Ferrell, S. M., Lynne, C. M.
& Brackett, N. L. Inflammatory cytokine
concentrations are elevated in seminal plasma
of men with spinal cord injuries. J. Androl. 25,
250–254 (2004).
69. Cohen, D. R. et al. Sperm motility in men with
spinal cord injuries is enhanced by inactivating
cytokines in the seminal plasma. J. Androl. 25,
922–925 (2004).
70. Brackett, N. L., Cohen, D. R., Ibrahim, E.,
Aballa, T. C. & Lynne, C. M. Neutralization of
cytokine activity at the receptor level improves
sperm motility in men with spinal cord injuries.
J. Androl. 28, 717–721 (2007).
71. Ohl, D. A., Menge, A. C. & Jarow, J. P. Seminal
vesicle aspiration in spinal cord injured men:
insight into poor sperm quality. J. Urol. 162,
2048–2051 (1999).
72. Brackett, N. L., Davi, R. C., Padron, O. F.
& Lynne, C. M. Seminal plasma of spinal cord
injured men inhibits sperm motility of normal
men. J. Urol. 155, 1632–1635 (1996).
73. Brackett, N. L., Lynne, C. M., Aballa, T. C.
& Ferrell, S. M. Sperm motility from the vas
deferens of spinal cord injured men is higher than
from the ejaculate. J. Urol. 164, 712–715 (2000).
74. Qiu, Y., Wang, L. G., Zhang, L. H., Zhang, A. D.
& Wang, Z. Y. Quality of sperm obtained by penile
vibratory stimulation and percutaneous vasal
sperm aspiration in men with spinal cord injury.
J. Androl. 33, 1036–1046 (2012).
75. Iremashvili, V., Brackett, N. L., Ibrahim, E.,
Aballa, T. C. & Lynne, C. M. The choice of
assisted ejaculation method is relevant for the
diagnosis of azoospermia in men with spinal
cord injuries. Spinal Cord 49,55–59 (2011).
76. Bartak, V., Josifko, M. & Horackova, M. Juvenile
diabetes and human sperm quality. Int. J. Fertil.
20, 30–32 (1975).
77. Padron, R. S., Dambay, A., Suarez, R. & Mas, J.
Semen analyses in adolescent diabetic patients.
Acta Diabetol. Lat. 21, 115–121 (1984).
78. Ali, S. T., Shaikh, R. N., Siddiqi, N. A. &
Siddiqi, P. Q. Semen analysis in insulin-
dependent/non‑insulin‑dependent diabetic men
with/without neuropathy. Arch. Androl. 30,
47–54 (1993).
© 2015 Macmillan Publishers Limited. All rights reserved
REVIEWS
79. Delfino, M., Imbrogno, N., Elia, J., Capogreco, F.
& Mazzilli, F. Prevalence of diabetes mellitus in
male partners of infertile couples. Minerva Urol.
Nefrol. 59, 131–135 (2007).
80. Agbaje, I. M. et al. Insulin dependant diabetes
mellitus: implications for male reproductive
function. Hum. Reprod. 22, 1871–1877 (2007).
81. Safarinejad, M. R. Evaluation of endocrine
profile, hypothalamic‑pituitary‑testis axis
and semen quality in multiple sclerosis.
J. Neuroendocrinol. 20, 1368–1375 (2008).
82. La Vignera. S., Condorelli, R., Vicari, E., D’Agata, R.
& Calogero, A. E. Diabetes mellitus and sperm
parameters. J. Androl. 33, 145–53 (2012).
83. Shin, D. H. & Turek, P. J. Sperm retrieval
techniques. Nat. Rev. Urol. 10, 723–730 (2013).
84. Goldstein, M. & Tanrikut, C. Microsurgical
management of male infertility. Nat. Clin. Pract.
Urol. 3, 381–391 (2006).
85. Wosnitzer, M. S. & Goldstein, M. Obstructive
azoospermia. Urol. Clin. North Am. 41, 83–95
(2014).
86. Practice Committee of American Society for
Reproductive Medicine. Sperm retrieval for
obstructive azoospermia. Fertil. Steril. 90,
S213–S218 (2008).
87. Dieckmann, K. P., Heinemann, V., Frey, U.
& Pichlmeier, U. How harmful is contralateral
testicular biopsy?—an analysis of serial imaging
studies and a prospective evaluation of surgical
complications. Eur. Urol. 48, 662–672 (2005).
88. Donoso, P., Tournaye, H. & Devroey, P. Which is
the best sperm retrieval technique for non-
obstructive azoospermia? A systematic review.
Hum. Reprod. Update 13, 539–549 (2007).
89. Boomsma, C. M., Heineman, M. J., Cohlen, B. J.
& Farquhar, C. Semen preparation techniques
for intrauterine insemination. Cochrane
Database of Systematic Reviews, Issue 4.
Art. No.: CD004507. http://dx.doi.org/
10.1002/14651858.CD00450.pub2.
90. Duran, E. H., Morshedi, M., Taylor, S. &
Oehninger, S. Sperm DNA quality predicts
intrauterine insemination outcome: a
prospective cohort study. Hum. Reprod. 17,
3122–3128 (2002).
91. Cantineau, A. E., Cohlen, B. J. & Heineman, M. J.
Ovarian stimulation protocols (anti-oestrogens,
gonadotrophins with and without GnRH
agonists/antagonists) for intrauterine
insemination (IUI) in women with subfertility.
Cochrane Database of Systematic Reviews,
Issue 2. Art. No.: CD005356. http://dx.doi.org/
10.1002/14651858.CD005356.pub2.
92. Bensdorp, A. J., Cohlen, B. J., Heineman, M. J.
& Vandekerckhove, P. Intra-uterine insemination
for male subfertility. Cochrane. Database. Syst.
Rev. Issue: 4. Art No.: CD000360. http://dx.doi.
org/10.1002/14651858.CD000360.pub4.
93. Goverde, A. J. et al. Ovarian response to standard
gonadotrophin stimulation for IVF is decreased
not only in older but also in younger women in
couples with idiopathic and male subfertility.
Hum. Reprod. 20, 1573–1577 (2005).
94. Yeh, J., Leipzig, S., Friedman, E. A. &
Seibel, M. M. Results of in vitro fertilization
pregnancies: experience at Boston’s Beth Israel
Hospital. Int. J. Fertil. 35, 116–119 (1990).
95. Navot, D., Bergh, P. A. & Laufer, N. Ovarian
hyperstimulation syndrome in novel reproductive
technologies: prevention and treatment.
Fertil. Steril. 58, 249–261 (1992).
96. [No authors listed]. Assisted reproductive
technology in the United States: 1996 results
generated from the American Society for
Reproductive Medicine/Society for Assisted
Reproductive Technology Registry. Fertil. Steril.
71, 798–807 (1999).
REVIEWS
97. Schenker, J. G. & Ezra, Y. Complications of
assisted reproductive techniques. Fertil. Steril.
61, 411–422 (1994).
98. Fauser, B. C., Devroey, P. & Macklon, N. S.
Multiple birth resulting from ovarian stimulation
for subfertility treatment. Lancet 365,
1807–1816 (2005).
99. della Ragione, T. et al. Developmental stage
on day‑5 and fragmentation rate on day‑3 can
influence the implantation potential of top-
quality blastocysts in IVF cycles with single
embryo transfer. Reprod. Biol. Endocrinol. 5, 2
(2007).
100. Palermo, G., Joris, H., Devroey, P.
& Van Steirteghem, A. C. Pregnancies after
intracytoplasmic injection of single
spermatozoon into an oocyte. Lancet 340,
17–18 (1992).
101. Kupker, W. et al. Use of frozen-thawed testicular
sperm for intracytoplasmic sperm injection.
Fertil. Steril. 73, 453–458 (2000).
102. Cohen, J. et al. Cryopreservation of single
human spermatozoa. Hum. Reprod. 12,
994–1001 (1997).
103. Van Voorhis, B. J. et al. Effect of the total
motile sperm count on the efficacy and cost-
effectiveness of intrauterine insemination
and in vitro fertilization. Fertil. Steril. 75,
661–668 (2001).
104. Ohl, D. A. et al. Electroejaculation and assisted
reproductive technologies in the treatment
of anejaculatory infertility. Fertil. Steril. 76,
1249–1255 (2001).
10  |  ADVANCE ONLINE PUBLICATION
105. Sonksen, J. et al. Pregnancy after assisted
ejaculation procedures in men with spinal cord
injury. Arch. Phys. Med. Rehabil. 78, 1059–1061
(1997).
106. Lochner-Ernst, D., Mandalka, B., Kramer, G.
& Stohrer, M. Conservative and surgical semen
retrieval in patients with spinal cord injury.
Spinal Cord 35, 463–468 (1997).
107. Nehra, A., Werner, M. A., Bastuba, M., Title, C.
& Oates, R. D. Vibratory stimulation and rectal
probe electroejaculation as therapy for patients
with spinal cord injury: semen parameters and
pregnancy rates. J. Urol. 155, 554–559 (1996).
108. Dahlberg, A., Ruutu, M. & Hovatta, O.
Pregnancy results from a vibrator application,
electroejaculation, and a vas aspiration
programme in spinal-cord injured men.
Hum. Reprod. 10, 2305–2307 (1995).
109. Rutkowski, S. B. et al. A comprehensive
approach to the management of male infertility
following spinal cord injury. Spinal Cord 37,
508–514 (1999).
110. Kathiresan, A. S. et al. Pregnancy outcomes by
intravaginal and intrauterine insemination in 82
couples with male factor infertility due to spinal
cord injuries. Fertil. Steril. 96, 328–331 (2011).
111. Leduc, B. E. Treatment of infertility in 31 men
with spinal cord injury. Can. J. Urol. 19,
6432–6436 (2012).
112. Sonksen, J., Fode, M., Lochner-Ernst, D.
& Ohl, D. A. Vibratory ejaculation in 140 spinal
cord injured men and home insemination of their
partners. Spinal Cord 50, 63–66 (2012).
© 2015 Macmillan Publishers Limited. All rights reserved
113. Hultling, C. et al. Assisted ejaculation and in-vitro
fertilization in the treatment of infertile spinal
cord-injured men: the role of intracytoplasmic
sperm injection. Hum. Reprod. 12, 499–502
(1997).
114. Heruti, R. J. et al. Treatment of male infertility
due to spinal cord injury using rectal probe
electroejaculation: the Israeli experience.
Spinal Cord 39, 168–175 (2001).
115. Shieh, J. Y. et al. A protocol of
electroejaculation and systematic assisted
reproductive technology achieved high
efficiency and efficacy for pregnancy for
anejaculatory men with spinal cord injury.
Arch. Phys. Med. Rehabil. 84, 535–540
(2003).
116. Kathiresan, A. S. et al. Comparison of in vitro
fertilization/intracytoplasmic sperm injection
outcomes in male factor infertility patients with
and without spinal cord injuries. Fertil. Steril. 96,
562–566 (2011).
117. Raviv, G., Madgar, I., Elizur, S., Zeilig, G.
& Levron, J. Testicular sperm retrieval and
intra cytoplasmic sperm injection provide
favorable outcome in spinal cord injury
patients, failing conservative reproductive
treatment. Spinal Cord 51, 642–644 (2013).
Author contributions
M.F. researched data for and wrote the article. All
authors made substantial contributions to discussion
of content and reviewed/edited the manuscript
before submission.
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