This document summarizes fertility in men with Klinefelter syndrome. It discusses that: 1) Men with Klinefelter syndrome (47,XXY karyotype) typically show azoospermia, though sperm are rarely observed in ejaculate and exceptional spontaneous pregnancies have been reported. 2) With surgical sperm retrieval, sperm have been found in up to 56.7% of cases and used for successful pregnancies via ICSI. 3) There is a higher risk of chromosomal abnormalities in sperm and offspring due to the genetic nature of Klinefelter syndrome, including sex chromosome aneuploidies and increased autosomal aneuploidies.

1. UNIVERSITÀ DEGLI STUDI DI TORINO
A.O. Città della Salute e della Scienza di Torino – Molinette
Divisione Universitaria di Urologia - Direttore: Prof. B. Frea
S.S.C.V.D. per l’Andrologia – Responsabile: Dott. L. Rolle
RECUPERO DI SPERMATOZOI
NELLA SINDROME DI KLINEFELTER
Massimiliano Timpano

2. Fertility in Klinefelter syndrome
Practically all ejaculates from patients with 47,XXY
karyotype show azoospermia
Sperm are observed only rarely, and exceptional cases of
spontaneous paternity have been reported
Lanfranco et al., Lancet 2004; 364: 273-83

3. Reported pregnancies after ICSI treatment with
ejaculated spermatozoa of patients with non-mosaic
KS.
Lanfranco et al., Lancet 2004; 364: 273-83

4. Human Reproduction 11: 1644-9, 1996
Testicular sperm recovery
47,XXY Klinefelter patients.
in
nine
Tournaye H, Staessen C, Liebaers I, Van Assche E, Devroey
P, Bonduelle M, Van Steirteghem A.
Centre for Reproductive Medicine, University Hospital, Dutch-speaking Brussels Free University (Vrje
Universitet Brussel), Laarbeeklaan 101, B-1090 Brussels, Belgium

5. Reported pregnancies after ICSI treatment with
testicular spermatozoa of patients with KS.
Lanfranco et al., Lancet 2004; 364: 273-83

7. Natural history of seminiferous tubule degeneration in
KS
The degenerative process may start even during fetal life, as
studies of aborted fetuses at gestational ages 18–22 weeks
have shown (Murken et al., Lancet 1974 ; Coerdt et al., Pediatr
Pathol 1985).
In prepubertal KS boys, the focal nature of the degeneration
process is already evident, since the few seminiferous tubules
containing spermatogonia are surrounded by Sertoli-cell-only
tubules.
In KS, immature Sertoli cells are incapable during puberty of
transforming into the adult mature cell type.
Aksglaede et al., Hum Reprod 2006; 12:39-48
Wikstrom AM & Dunkel L, Horm Res 2008; 69:317-326

8. Natural history of seminiferous tubule degeneration in
KS
Major histological changes in the testes coincide with the
pubertal activation of the pituitary-gonadal axis.
With age, fibrosis and hyalinization of the interstitium and
peritubular connective tissue increases, and already in 12- to
14-year-old KS boys, huge hyperplastic Leydig cells can be
visible in testicular biopsies
Wikstrom et al., JCEM 2004
The degeneration of germ cells in KS may be because of a
primary effect of the extra X chromosome on the development
and function of the germ cells or adverse influence on the
supporting somatic cells including the Leydig and Sertoli cells.
Aksglaede et al., Hum Reprod 2006; 12:39-48
Wikstrom AM & Dunkel L, Horm Res 2008; 69:317-326

13. • Volume testicolare
NO
• FSH
• Inibina B
• Rapporto inibina B/FSH
NO
NO
NO

14. With the aid of an operating microscope for microdissection (micro-TESE),
the sperm retrieval rate was
successful in 56.7% of 74 cases
with non-mosaic KS.
Urology 2006; 68: 1082-1086

15. Testicular tissue may be successfully cryopreserved
in patients with non-mosaic KS without significantly
compromizing fertilization and implantation rates.
As germ cell depletion is already evident in the testes
of 47,XXY infants and rapidly progresses,
cryopreservation of semen samples may preserve future fertility
in those young KS men identified before the time
at which they present with infertility.
Tournaye et al., Int J Androl 1997; 20:69-73
Friedler et al., Hum Reprod 2001; 16:2616-2620
Staessen et al., Hum Reprod Update 2003; 9:319-330
Kamischke et al., J Androl 2004; 25:586-592

16. 25 pazienti con cariotipo 47, XXY – età media 35 anni
Recupero positivo in 8 pazienti (32%)
• FSH
23 UI/L
• Volume 4 cc
• FSH
30.5 UI/L
• Volume 3.5 cc
• Età
• Età
31 anni
38 anni
Casistica personale

17. In studies of chromosomal abnormalities
in
ejaculated spermatozoa from patients with KS
the
incidence of sex chromosomal hyperploidy
varied
from 0.9% to 2.5% in the mosaic form
and from
2.5% to 21.6% in the non-mosaic form.
The proportion of hyperploid spermatozoa
men with KS does not correlate with the proportion
47,XXY cells in somatic tissues.
Overall, a higher risk of fathering a 47,XXY or
47,XXX child after successful fertilization
treatment has to be taken into account.
in
of

18. An increased incidence of autosomal aneuploidies
in spermatozoa from subjects with non-mosaic KS
has been demonstrated.
Hennebicq et al. (2001) described a higher frequency of
disomy 21 in the spermatozoa of a non-mosaic Klinefelter
patient, thus indicating an important risk of trisomy 21
in offspring of patients with KS when these patients
were candidates for ICSI.
Morel et al. (2003) found a significant difference in the
frequency of autosomal disomy for chromosomes 13, 18
and 21 in Klinefelter patients.

19. FERTILITY IN KLINEFELTER SYNDROME
Patients with Klinefelter syndrome, including the non-mosaic type,
may no longer be considered infertile a priori, as ICSI offers the
opportunity for procreation even when spermatozoa in the
ejaculate are lacking.
Surgical sperm retrieval has revealed spermatozoa in up to one
half of non-mosaic Klinefelter patients selectively referred to
centers specialized in assisted reproduction techniques.
The incidence of sex chromosomal hyperploidy and autosomal
aneuploidies is higher in spermatozoa from Klinefelter patients
than from normal men.
Chromosomal errors may be transmitted to the offspring
of men with Klinefelter syndrome.
The genetic implications of the fertilization procedures including
pretransfer or prenatal genetic evaluation must be explained to the
patients and their partners.

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