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ManageMent Update
Infertility in Patients With Klinefelter
Syndrome: Optimal Timing for Sperm
and Testicular Tissue Cryopreservation
Dorota J. Hawksworth, MD, MBA,1 April A. Szafran, MD, PhD,1 Philip W. Jordan, PhD,2
Adrian S. Dobs, MD,3 Amin S. Herati, MD1
1Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD; 2Department of Biochemistry and
Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD; 3Department
of Endocrinology, Johns Hopkins Medical Institutions, Baltimore, MD
Male factor infertility is a complex issue presenting many diagnostic and management
challenges. It is responsible for about 50% of all causes of infertility and thus carries
significant medical, financial, and psychological implications for the couples struggling
with conception. Klinefelter syndrome is the most common chromosomal male anomaly
associated with male infertility. This review focuses specifically on non-obstructive azo-
ospermia secondary to Klinefelter syndrome and discusses controversies surrounding
fertility management in patients with this genetic disorder.
[Rev Urol. 2018;20(2):56–62 doi: 10.3909/riu0790]
© 2018 MedReviews®, LLC
KEY WORDS
Klinefelter syndrome • Non-obstructive azoospermia • Sperm retrieval
Infertility, defined as failure to conceive after 1 year
of unprotected sexual intercourse, is estimated to
affect up to 15% of couples worldwide with a male
factor implicated in approximately 50% of cases.1-3
Male infertility can manifest from numerous etiolo-
gies ranging from obstruction of the vasa deferentia
to non-obstructive etiologies, such as genetic anom-
alies resulting in testicular dysfunction.
An endocrine evaluation, consisting of a serum
testosterone and follicle-stimulating hormone (FSH)
level, is part of the standard evaluation of the infer-
tile male as it can assist in establishing an underlying
diagnosis and can also guide medical and surgi-
cal therapy. With male infertility, FSH level values
inversely reflect the quality of spermatogenesis. An
FSH value over 7.6 IU/mL has been shown to be a
strong predictor of spermatogenic failure, whereas
a normal FSH value is predictive of normal sper-
matogenesis. Schoor and colleagues showed that
91% of men with azoospermia and FSH value less
56 • Vol. 20 No. 2 • 2018 • Reviews in Urology
4170018_02_RIU0790_V2_ptg01.indd 56 9/11/18 5:15 PM
49,XXXXY), or possess partial
fragments of supranumery X
chromosomes (eg, 47,X,iXq,Y).10,12
Whereas some mosaic patients
present with less severe infertility
phenotypes and possess reduced
concentrations of sperm on SA
(oligozoospermia), most men with
KS are azoospermic and for pater-
nity reasons require assisted repro-
ductive technologies (ART).
Natural History of KS
Patients may be diagnosed with KS
during different stages of their lives,
ranging from the prenatal period
via amniocentesis to adulthood.
Most patients undergo chromo-
somal evaluation in their adoles-
cence or adulthood, when delayed
or incomplete puberty or infertil-
ity arise. However, an increasing
number of KS patients are detected
prenatally secondary to their par-
ents delaying reproduction due to
socioeconomic factors and gender
roles changes in the work force.13
As a consequence of increasing
maternal age, more amniocente-
ses and chorionic villi biopsies are
performed thus increasing prenatal
diagnoses of KS.
In addition to chromosomal
analysis, all men with KS should
undergo a thorough reproductive
workup with hormonal and SA
evaluations. Levels of testosterone,
luteinizing hormone (LH), FSH,
estradiol (E2), prolactin, sex hor-
mone binding globulin (SHBG),
and inhibin B should be measured.
It has been documented that pre-
pubertal males have normal lev-
els of testosterone, LH and FSH,
whereas at puberty testosterone
levels start to decline and FSH and
LH rise. In addition to a hormonal
evaluation, at least two semen sam-
ples should be analyzed.
Testicular function in KS presents
a story of progressive degeneration.
Ultimately, this degeneration leads
to infertility as the normal testicular
than 7.6 IU/mL had an obstructive
etiology explaining their infertil-
ity. Similarly, elevated FSH values
also correlate with a lower prob-
ability of sperm retrieval rates with
testicular sperm extraction (TESE)
procedures.4,5
Although decreasing semenpara -
meters, such as sperm concentra-
tion, and rising FSH values can be
used as an indication of progres-
sive spermatogenic failure, it is not
a perfect biomarker of spermato-
genesis. Ramasamy and colleagues
showed that among men with non-
obstructive azoospermia (NOA),
sperm retrieval rates using micro-
surgical testicular sperm extraction
(mTESE) were higher among men
with an FSH value of .15 IU/mL
than men with an FSH ,15 IU/mL.6
In this study, three men with FSH
values .90 IU/mL had successful
sperm extraction. These findings
demonstrate the limited utility of
FSH and the importance of micro-
surgical examination in men who
are actively seeking fertility.
In this review, we focus spe-
cifically on non-obstructive azo-
ospermia secondary to Klinefelter
syndrome (KS), which is character-
ized by a high FSH level, and dis-
cuss the optimal timing of sperm
retrieval in these patients, many
of whom are not actively seeking
fertility.
Genetic Basis for Male
Infertility and Klinefelter
Syndrome
Overall, genetic and genomic
abnormalities may contribute up to
50% of male factor infertility and
infertile men have up to 10-fold
higher prevalence of chromosomal
abnormalities when compared
with fertile men.7 Aneuploidy is
the most common chromosomal
error identified in infertile men
and the most common of those
are KS, XYY syndrome, XX male
syndrome, mixed gonadal dysgen-
esis, autosomal translocations, and
Y-chromosome microdeletions.8
KS is the most common chromo-
somal male anomaly, the most
common sex chromosome disorder
of infertile men, and as such, it spe-
cifically results in NOA.
A comprehensive hormonal
evaluation of the patients with
NOA sub-classifies them into two
groups: those with hypogonado-
tropic hypogonadism (HH) and
those with hypergonadotropic
hypogonadism. Hypergonadotropic
hypogonadism is caused by an
intrinsic testicular dysfunction
and its causes include genetic
defects (aneuploidy, Y-chromosome
microdeletions), varicocele, expo-
sure to gonadotoxins, orchitis,
prior surgery/trauma, or testicular
torsion.9 Of these causes, KS is the
most common aneuploidy in men
resulting in male factor infertil-
ity and is characterized by a male
karyotype with one or more addi-
tional X chromosomes. The disease
affects 1 in 600 newborn males and
typically manifests in adolescence
or early adulthood with charac-
teristic findings of hypergonado-
tropic hypogonadism and primary
infertility.10,11 On physical exami-
nation, patients usually have nor-
mal or tall stature, gynecomastia,
and small testes. Additionally, these
patients may have mild cognitive
impairment. Due to a wide varia-
tion in clinical presentation, many
patients may go undiagnosed. The
diagnosis, when made, depends on
a combination of history, physical
examination, semen analysis (SA),
and, ultimately, karyotype testing.
With increasing utilization of pre-
natal or other genetic testing, the
detection of KS is likely to increase.
The majority of patients carry
a 47XXY karyotype, whereas the
remaining 10% to 20% are mosa-
ics (46,XY/47,XXY), have higher
grade aneuploidy (48,XXXY,
Vol. 20 No. 2 • 2018 • Reviews in Urology • 57
Infertility in Patients With Klinefelter Syndrome
4170018_02_RIU0790_V2_ptg01.indd 57 9/11/18 5:15 PM
architecture is replaced initially by
either tubular atrophy, sclerosis, or
maturation arrest and ultimately
degenerates to fibrosis and hya-
linized tissue.14 Numerous stud-
ies demonstrate already reduced
numbers of germ cells in biopsies of
47XXY fetal testes evaluated dur-
ing the prenatal period, between
18 and 22 weeks of gestation.15,16
This deficit is further augmented in
non-descended testes. In the neo-
natal period, based on lower levels
of serum testosterone during the
initial months of life in non-mosaic
47XXY patients, Leydig cell dys-
function is postulated to play a sig-
nificant role.17 Sertoli cells, however,
appear to be histologically intact in
both the fetal and neonatal periods
in subjects with a 47XXY genotype.
These subtle changes may create a
platform for the later testicular fail-
ure that ensues in adolescence.
The transition to rapid deterio-
ration in production of both germ
cell lines as well as in the histologi-
cal composition of the testes in KS
patients occurs during puberty.
Wilkstrom and colleagues dem-
onstrated that prepubertal KS
patients with bilateral descended
testes retained germ cells on biopsy,
though at lower levels than normal
children.18 The subjects who had
undergone puberty at the time of
biopsy had no germ cells present and
had concomitant degeneration of
Sertoli cells and hyalinization of the
seminiferous tubules.18 Therefore,
activation of the hypothalamic-
pituitary-gonadal (HPG) axis
(Figure 1) and stimulation of the
gonadal tissue appears to accelerate
testicular demise in puberty. This is
thought to arise from aneuploidy-
induced non-homologous recom-
bination and subsequent activation
of apoptosis-related genes within
the spermatogonial cell line as
spermatogonia differentiate into
primary spermatocytes and prog-
ress through meiosis.12,19
While the molecular mecha-
nisms underlying spermatogenic
failure are poorly understood,
recent investigations into the tran-
scriptome have highlighted many
candidate genes that are dysregu-
lated in KS spermatogonial cells.
D’Aurora and colleagues analyzed
the transcriptome of testicular biop-
sies obtained from three men with
KS and compared them with the
transcriptome of three controls.12
Differential expression was observed
in 1050 genes, with 747 genes down-
regulated and 303 up-regulated
genes. One-third of the genes up-
regulated were linked to apoptosis.
Gene cluster and pathway analysis
showed four possible mechanisms
responsible for hypospermatogen-
esis in KS patients: impaired devel-
opment of spermatogonia to mature
spermatozoa, defects in the testis
architecture, pathophysiology of the
testis environment, and apoptosis
of the germinal and somatic cells.20
Of all the dysregulated genes, four
genes mapped to the X chromo-
some including solute carrier family
25 member 5gene (SLC25A5) on the
Par1 region, phosphoribosyl pyro-
phosphate synthetase 1 (PRPS1),
TSC22 domain family member 3
(TSC22D3), and A-kinase anchoring
protein 4 (AKAP4). Other important
dysregulated genes include down-
regulation of the cAMP responsive
element modulator (CREM) gene,
which is an important transcrip-
tion factor for spermatogenesis,
the HORMA domain containing
2 (HORMAD2) gene, which sur-
veils the synaptic events during
prophase of meiosis, and the cyclin
A1 (CCNA1) gene, which is required
for spermatocyte passage into the
first meiotic division.21,22 Compared
with controls, the majority of down-
regulated genes were those essential
for spermatogenesis, whereas apop-
totic genes were common among
those up-regulated.
The spermatogonia of the testis
can possess significant heterogene-
ity, even among patients with sex
chromosome trisomy (SCT). Recent
Figure 1. Representation of hypothalamus-pituitary-gonadal axis.
T
PITUITARY
SERTOLI CELL LEYDIG CELL
FSH LH
GnRH
E2
T
INHIBIN
ABP
A
A – Aromatase
ABP – Androgen Binding Protein
E2 – Estradiol
FSH – Follicle Stimulating Hormone
GnRH – Gonadotropin Releasing Hormone
LH – Luteinizing Hormone
T - Testosterone
HYPOTHALAMUS
58 • Vol. 20 No. 2 • 2018 • Reviews in Urology
Infertility in Patients With Klinefelter Syndrome
continued
4170018_02_RIU0790_V2_ptg01.indd 58 9/11/18 5:15 PM
data from Hirota and colleagues
demonstrate a mechanism for
spermatogonia to escape the mas-
sive wave of apoptosis that occurs
during puberty in KS patients
(Figure 2).23 To demonstrate this
phenomenon, fibroblasts derived
from control and sex chromosome
trisomy mice were dedifferenti-
ated to form-induced pluripotent
stem cells (iPSCs). Fluorescent in
situ hybridization performed on
iPSCs derived from SCT fibroblasts
showed a propensity for sex chro-
mosome loss over autosomal chro-
mosome loss, returning the iPSC
cells to a euploid state. This concept
of trisomic chromosome loss has
been similarly observed in human
trisomic cell cultures obtained and
reprogrammed into iPSC from the
fibroblasts of patients with Down
syndrome.23,2 4 Hirota and col-
leagues provide an important proof
of concept for the mechanism by
which KS patients may retain the
ability to preserve spermatogenesis
into later years of life.23
Pros and Cons of Early
Fertility Management
It is well established that men with
KS are born with spermatogonia
and that the onset of puberty is
associated with increased rates of
progressive testicular germ cell
depletion and subsequent decline in
testicular function. It is also widely
accepted that small, patchy distri-
bution of spermatogenesis exists
even in the adult men’s testes, as
spermatozoa have been found both
in the testicular tissue and occa-
sionally in the ejaculate. At present,
thanks to the advances in testicular
sperm extraction (TESE) and intra-
cytoplasmic sperm injection (ICSI)
techniques, approximately 50%
of men with KS will have sperm
detected with TESE/microTESE,
of which a 50% pregnancy and live
birth rate can be expected.25
Based on prior data indicating
that younger age is a major posi-
tive predictive factor for success-
ful sperm retrieval, it has been
advocated that fertility preserva-
tion should be offered to prepu-
bertal and adolescent boys with
KS. Because the testicular func-
tion decline begins in puberty and
worsens in adulthood, intervention
prior to or at the beginning of this
decline should yield the most suc-
cessful sperm retrieval. Sperm has
been identified in 70% of ejaculated
semen specimens in adolescents
with KS aging 12 to 20 years.26
Therefore, if younger patients are
able and willing to provide an
ejaculated specimen, they may ulti-
mately avoid more invasive surgi-
cal interventions in their future.
Testicular dissection for sperm
harvesting has well documented
negative effects and those may
result in irreversible scarring and
atrophy, potential testicular injury
or loss, as well as further decline
in testicular function and resulting
decrease in testosterone levels.27
The need for chronic hormonal
therapy (HT) in these patients
further complicates their fertility
potential. HT is often initiated in
boys with KS at around 12 years of
age, especially if they exhibit evi-
dence of hypergonadotropic hypo-
gonadism. Androgen replacement
at the time of puberty supports
normal development of secondary
sexual characteristics, body habitus,
and results in overall improvement
in energy levels. Furthermore, long-
term HT prevents development
of significant medical issues, to
include osteoporosis, diabetes, obe-
sity, and depression. Excess extra-
testicular androgens, however,
further suppress already impaired
spermatogenesis in patients with
KS. It has been postulated that
sperm harvest at time of puberty,
or prior to initiation of HT provides
best chance of success.26 Although
new approaches to medical man-
agement of these patients’ hypo-
gonadism allows successful sperm
harvest, despite long-term andro-
gen supplementation, sperm cryo-
preservation should be offered to
all adolescents with KS irrespective
of their hormonal status, particu-
larly those who are either consider-
ing or receiving HT.
Currently, there are no estab-
lished guidelines for appropriate
timing or and harvesting technique
choices, and only sperm cryo-
preservation is considered accepted
standard of care. An important
consideration in determining the
FIBROBLAST–47XXY
iPSC iPSC iPSC
47XXY
iPSC iPSC iPSC
46XY/46XX
PASSAGE 2-6
DIFFERENTIATION TO
EPIBLAST-LIKE STATE
PGCLC
46XY/46XX
TRANSPLANT
PGCLC
PGCLC
SEMINIFEROUS TUBULE
Figure 2. Trisomic chromosome loss and development of spermatozoa from euploid primordial germ cell–like
cells (PGCLC) from induced pluripotent stem cells (iPSC). Methodology adapted from Hirota T et al.23
Vol. 20 No. 2 • 2018 • Reviews in Urology • 59
Infertility in Patients With Klinefelter Syndrome
4170018_02_RIU0790_V2_ptg01.indd 59 9/11/18 5:15 PM
optimal timing of microTESE in
KS patients is whether fresh or
cryopreserved-thawed testicular
sperm yields different outcomes
with in vitro fertilization (IVF) and
ICSI. Although few studies have
compared ICSI outcomes between
fresh and cryopreserved-thawed
testicular spermatozoa from KS
patients, the available studies show
comparable outcomes. In one study
by Friedler and colleagues, fresh
testicular spermatozoa resulted in
improved two pronuclear fertil-
ization rate (66% vs 58%), embryo
cleavage rate (98% vs 90%), and
embryo implantation rate (33.3% vs
21.4%) over cryopreserved-thawed
testicular spermatozoa; however,
this difference was not statisti-
cally significant.28 These findings
are consistent with those of a 2017
meta-analysis by Corona and col-
leagues, who showed no difference
in pregnancy and live birth rates
between fresh and cryopreserved-
thawed testicular spermatozoa
using data extracted from 1248
KS patients from 37 studies, and
a 2014 meta-analysis by Ohlander
and coworkers, who observed no
statistically significant difference
between fertilization and clini-
cal pregnancy rates using the two
types of spermatozoa in men with
NOA.25,29 Based on these limited
studies, we believe that cryopre-
served-thawed testicular sperm
is a viable option for KS patients
who are not actively planning for
conception but wish to retain their
sperm for future use.
Other, more experimental ap-
proaches, such as testicular tissue
or spermatogonial stem cell cryo-
preservation with subsequent goal
of transplantation, can be offered to
patients only as part of an institu-
tional research protocol. We antici-
pate that pre-pubescent fertility
management will gain in importance
as more KS patients are detected
prenatally via amniocentesis or
chorionic villi biopsy. Alternative
strategies may also become avail-
able to prevent the activation of
spermatogonia and their subse-
quent apoptosis. These approaches
to fertility preservation in young
adolescent males are also laden with
significant technical challenges and
ethical controversy. Young patients
may not be emotionally mature to
consider future fertility issues, may
not be able or willing to provide an
ejaculated semen sample, and may
be too afraid of any invasive surgi-
cal interventions. Specimen storage
fees may also carry a significant
long-term financial burden on both
the patients and their parents. At
this point, fertility and hormonal
management should be offered to
KS boys as early as 12 years of age.
With proper counseling, education
and multidisciplinary approach to
these patients’ complex issues, their
future reproductive and overall
health can be successfully managed
long term.
Strategies to Optimize
Sperm Retrieval Rates
Unsuccessful sperm recovery
has negative impact on patients
and their partners from an emo-
tional and a financial standpoint.
Literature indicates that surgical
sperm retrieval rates (SRR) in men
with KS are estimated to be approx-
imately 51%, ranging from 28% to
70% with a pregnancy and live
birth rate of 50%.25 Recent surgical
advances with introduction of sur-
gical microscope and micro-TESE,
optimization of ART techniques,
improvements in medical manage-
ment of hypogonadism, as well as
more proactive early approach to
management of these patients all
contribute to improved SRR and
ultimately fertility outcomes.
The use of high-power surgi-
cal microscope (magnification
of 20×-25×) and development
of micro-TESE has reduced the
amount of testicular tissue needed
and has minimized the damage
to the testicular blood supply and
resulted in much higher over-
all SRR. Schlegel and colleagues
reported a significant statistical
difference in the overall SRR when
comparing patients undergoing
standard TESE to those under-
going micro-TESE (45% vs 63%)
and further demonstrated much
higher spermatozoa yield from
smaller, micro-dissected samples
(64,000 vs 160,000).30 Moreover,
sperm retrieval rates in patients
with KS have been demonstrated
to be equivalent to those men who
have NOA secondary to other
reasons.31 Unfortunately, micro-
TESE requires highly specialized
microsurgical training and close
cooperation with the reproduc-
tive endocrinologist and the ART
team. As such, patients requiring
micro-TESE are usually referred to
high-volume, specialized infertility
centers.
Normal testosterone levels have
been found to be an independent
factor in improving SRR. Currently,
the primary goal of medical man-
agement in men with hypergonad-
otropic hypogonadism, in addition
to correcting their hypogonad-
ism, is to improve the quantity
and quality of the retrieved sperm.
Antiestrogens (clomiphene citrate,
tamoxifen), aromatase inhibitors
(testolactone, anastrozole), and
gonadotropins (recombinant FSH
and hCG) have been evaluated in
patients with NOA and KS.
Non-steroidal antiestrogens block
the feedback inhibition of estro-
gen on the pituitary, resulting in
increased levels of LH and FSH
and subsequent rise in testoster-
one. Clomiphene citrate has been
used in severely oligozoospermic
men and thus far, only one series
evaluated its use in NOA patients.32
Clomiphene citrate enabled the
60 • Vol. 20 No. 2 • 2018 • Reviews in Urology
Infertility in Patients With Klinefelter Syndrome
continued
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References
1. Jarow J, Sigman M, Kolettis PN, et al. The optimal
evaluation of the infertile male: AUA Best Practice
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2. Templeton A, Fraser C, Thompson B. The epidemiol-
ogy of infertility in Aberdeen. BMJ. 1990;301:148-152.
3. World Health Organization. Programme of Maternal
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primary and secondary infertility. Gene va: World
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4. Schoor RA, Elhanbly S, Niederberger CS, Ross LS. The
role of testicular biopsy in the modern management of
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5. Bromage SJ, Falconer DA, Lieberman BA, et al. Sperm
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6. Ramasamy R, Lin K, Gosden LV, et al. High serum
FSH levels in men with nonobstructive azoospermia
does not affect success of microdissection testicular
sperm extraction. Fertil Steril. 2009;92:590-593.
7. Yatsenko AN, Yatsenko SA, Weedin JW, et al. Compre-
hensive 5-year study of cytogenetic aberrations in 668
infertile men. J Urol. 2010;183:1636-1642.
8. O’Flynn O’Brien KL, Varghese AC, Agarwal A. The
genetic causes of male factor infertility: a review. Fertil
Steril. 2010;93:1-12.
9. Kumar R. Medical management of non-obstructive azo-
ospermia. Clinics (Sao Paulo). 2013;68(suppl 1):75-79.
10. Foresta C, Galeazzi C, Bettella A, et al., Analysis of
meiosis in intratesticular germ cells f rom subjects
affected by classic Klinefelter’s syndrome. J Clin Endo-
crinol Metab. 1999;84:3807-3810.
11. Klinefelter HF, Reifenstein EC, Albright F. Syndrome
charact erized by gynec omastia, aspermatoge n-
esis without aledyigism and increased secretion of
follicle-stimulating hormone. J Clin Endocrinol Metab.
1942;2:615-627.
12. D’Aurora M, Ferlin A, Garolla A, et al. Testis tran-
scriptome modulation in Klinefelter patients with
hypospermatogenesis. Sci Rep. 2017;7:45729.
13. United States Census Bureau. Childlessness rises for
women in their early 30s. https://www.census.gov
/newsroom/blogs/random-samplings/2017/05/
childlessness_rises.html. Posted May 3, 2017. Accessed
May 30, 2018.
14. Aksglaede L, Link K, Giwercman A, et al. 47, XXY
Klinefelter syndrome: clinical characteristics and age-
specific recommendations for medical management.
Am J Med Genet C Semin Med Genet. 2013;163C:55-63.
detection of ejaculated sperm in
two-thirds of men who were origi-
nally NOA and diagnosed with
either maturation arrest or hypo-
spermatogenesis on initial testicu-
lar biopsy. However, it is important
to emphasize that KS men often
have elevated FSH values and are
not candidates for clomiphene
citrate therapy.
Exogenous gonadotropins de-
crease the endogenous gonadotro-
pin levels and in turn “re-set” FSH
and LH receptors in the Sertoli and
Leydig cells, respectively, ultimately
resulting in their improved func-
tion. Ramasamy and colleagues
reported improved TESE outcomes
in patients with NOA and KS who
received gonadotropin therapy.6
Testosterone and other andro-
gens are converted into E2 by aro-
matase, an enzyme present in the
liver, adipose tissue, and testes.
Elevated E2 levels further suppress
LH and FSH secretion from the
pituitary and inhibit testosterone
biosynthesis. Aromatase inhibitors,
at doses of 1 mg anastrozole daily,
are designed to block the conver-
sion of androgens to E2 and thus
further re-establishing a testoster-
one and E2 (T/E) balance. Although
significant improvements in sperm
counts were noted in men with
severe oligozoospermia, men with
NOA had no such benefit. The
experts argue, however, that use of
non-steroidal aromatase inhibitor
(anastrozole) specifically, results in
improved intra-testicular testoster-
one levels that further improve SRR
over a period of 3 months.
In conclusion, use of any of the
non–testosterone-based formula-
tions may be considered in KS men
planning on surgical sperm extrac-
tion. The selection of this type of
therapy and the decision to start it
should be made on individual basis,
following appropriate patient coun-
seling, especially because current
clinical evidence for this indica-
tion is not well supported by large
randomized, placebo-controlled
studies.
Conclusions
KS results in infertility in all
affected men. Early fertility preser-
vation, although currently not
standard of care, is recommended,
as sperm retrieval rates have been
higher in younger patients.
Complex, multidisciplinary care
should be provided to these patients
to optimize their overall health sta-
tus in addition to their ability to
father children.
Main Points
•Klinefeltersyndrome(KS)isthemostcommonchromosomaldisorderinmenandisassociatedwith
hypergonadotropichypogonadismandinfertility.
•EarlyhormonaltherapyisrecommendedforpatientswithKStoassurenormalpubertyandpreventlong-term
consequencesofhypogonadism.
•Cryopreservationofejaculatedsamplesortesticulartissuesamplesshouldbeofferedtoallyoung,post-
pubescentKSmenwhoarestartingorconsideringandrogenreplacementtherapy.
•Improvementsinmicrosurgicalspermretrievalandassistedreproductivetechniques,inadditiontomanagement
ofpatients’hypogonadismwithnon–testosterone-basedformulationsandinterventionsofferedinadolescence
allcontributetosignificantimprovementsinspermretrievalratesandprovidemaximumfuturefertilitypotential.
Vol.20No.2•2018•ReviewsinUrology•61
Infertility in Patients With Klinefelter Syndrome
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28. Friedler S, R aziel A, Strassburger D, et al. Outcome of
ICSI using fresh and cryopreserved-thawed testicular
spermatozoa in patients with non-mosaic Klinefelter’s
syndrome. Hum Reprod. 2001;16:2616-2620.
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