Managing infertility in patients with Klinefelter syndrome

Abstract

Klinefelter syndrome (KS) is the most frequent chromosomal abnormality with a prevalence of 150 per 100,000 males. It is now well known that the phenotype of Klinefelter adults varies from individual to individual and one registry study indicates that approximately 75% of KS subjects are not diagnosed probably because of very mild phenotypes. Due to seminiferous tubule fibrosis KS patients have small testes and are infertile because of azoospermia (>90%) or severe oligozoospermia (<10%). Adoption or heterologous insemination has been used in the past to achieve paternity. Currently it is well known that with TESE/micro-TESE (TESE = TEsticular Sperm Extraction) spermatozoa can be found in the testes of 28–67% of KS patients. Predictive factors of sperm retrieval success/failure, such as reproductive hormone plasma levels, testis volume and age, have been evaluated without any positive results. By combining TESE/micro-TESE with intracytoplasmic sperm injection an average of 50% of these patients have the possibility of fathering children and the birth of more than 150 children with normal karyotype has been reported in the last 20 years. However couples with a Klinefelter partner must be informed of the increased risk of autosomal/sex chromosomes aberrations in the sperm and embryos and of the possibility of preimplantation genetic diagnosis which is currently suggested by a minority of authors.

Keywords::

• azoospermia
• chromosomal abnormalities
• fertility preservation
• hypogonadism
• infertility
• Klinefelter
• preimplantation genetic diagnosis
• TESE

Acknowledgements

The authors gratefully acknowledge the help of C Krausz for reviewing the manuscript.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• About 90% of Klinefelter syndrome (KS) cases have a 47,XXY karyotype and 10% have 46,XY/47,XXY mosaicism.

• The majority of KS cases are diagnosed in adult life during the work-up of couple infertility.

• The clinical phenotype of KS is highly variable; however, the presence of small, firm testes is a constant clinical feature.

• Low testosterone levels are present in the majority of KS patients (63–85%), and early testosterone treatment is important for general health.

• Infertility in KS is due to the absence of spermatozoa in the ejaculate in more than 90% of subjects.

• The chance of getting a few sperm by repeated semen collections is low but higher in adult than in adolescent KS patients.

• The most common approach to achieving a pregnancy is TEsticular sperm extraction (TESE)/micro-TESE followed by intracytoplasmic sperm injection.

• There are no predictive factors of sperm retrieval by TESE/micro-TESE. The overall chance of sperm retrieval has been reported as being between 28–57%.

• Autosomal and sex chromosomal abnormalities are two- to threefold more frequent in spermatozoa of KS patients than in controls, but most of the testicular sperm retrieved by TESE/micro-TESE demonstrated a normal karyotype.

• It has been reported that more than 150 children with normal karyotype have been born from a KS father in the last 20 years.

• Genetic counseling to couples with a Klinefelter partner is recommended.