Klinefelter syndrome: fertility considerations and gaps in knowledge

Klinefelter syndrome: fertility considerations and gaps in knowledge

Leena Nahata1, Richard N. Yu2, Laurie E. Cohen3

1Division of Endocrinology, Nationwide Children’s Hospital, 700 Children’s Dr, Columbus, USA; 2Department of Urology, 3Division of Endocrinology, Boston Children’s Hospital, Boston, MA, USA

Correspondence to: Leena Nahata, MD. Division of Endocrinology, Nationwide Children’s Hospital, 700 Children’s Dr, Columbus, USA. Email: leena.nahata@nationwidechildrens.org.

Submitted Jun 08, 2016. Accepted for publication Jun 17, 2016.

doi: 10.21037/tp.2016.06.06

To the Editor:

We would like to thank Drs. Rogol and Skakkebaek for their timely and insightful commentary about medical and ethical issues with regard to sperm retrieval in adolescents with Klinefelter syndrome (KS) (1); the authors present key points discussed at the recent International Workshop on Klinefelter syndrome, in addition to summarizing our pilot clinical trial investigating sperm retrieval rates in adolescents and young adults with KS published in The Journal of Pediatrics (2,3). As was acknowledged in the original manuscript, Drs. Rogol and Skakkebaek emphasize potential selection bias in the study, as the sample size was small and many of the eligible subjects declined to participate due to “lack of psychological readiness to focus on fertility”; additionally, none of the patients had been treated with testosterone, indicating a “milder” end of the spectrum (1,2). The potential impact of prior testosterone therapy and other agents on sperm retrieval in this population was identified as a necessary issue for investigation (1,4).

Prospective studies in this area have been limited due to the rarity of making the KS diagnosis early in life, in addition to challenges associated with recruiting adolescents and young adults with KS for fertility related research. According to a 2011 study by Maiburg et al., adults with KS were interested in fathering children and were willing to undergo testicular sperm extraction (TESE) (5). Recent research, however, demonstrates a discrepancy between attitudes of parents and physicians versus those of younger individuals with KS; while most parents of children with KS and pediatricians favored pursuing TESE in a pubertal minor, adolescents with KS reported a lack of interest in fertility and required at least three medical consultations prior to becoming involved in fertility preservation (6,7). Thus, in order to successfully complete prospective studies to investigate predictors of successful TESE and the impact of exogenous testosterone or other treatments on sperm retrieval, reproductive priorities and potential barriers to acceptance of fertility preservation procedures need to be better understood in this particular population.

Most of the pediatric literature with regard to fertility has been done in oncology, where many males are able to produce an ejaculate for sperm cryopreservation. It is notable that this is generally not an option for individuals with KS, which is in itself, a potential barrier. Additionally, neurocognitive dysfunction is common in KS, and studies have shown lower quality of life and self-esteem, all of which could impact attitudes about reproductive health and willingness to participate in research studies (8). Thus, validated surveys and qualitative methodology should be implemented to further explore key factors such as reproductive concerns, romantic relationships, sexual function, and psychosocial well-being among adolescents and young adults with KS at different ages/developmental stages.

Based on current literature, the recommended age range to consider sperm retrieval among individuals with KS is 15–30 years (3,9,10). Medical professionals who care for individuals with KS have a responsibility to become educated on this topic and offer referrals to fertility specialists to (I) provide comprehensive counseling about the current options along with acknowledging their experimental nature; and (II) consider potential ethical implications in each individual case (6,11). As Drs. Rogol and Skakkebaek point out, many questions remain unanswered, including the viability and quality of sperm retrieved from this patient population after many years of freezing (1). Opportunities for early diagnosis of KS will likely increase due to increasing use of prenatal testing, and more patients and families may inquire about the potential risks/benefits of cryopreservation of sperm. Thus, longitudinal follow-up to assess utilization of the frozen sperm, pregnancy rates, and outcomes, will be critical for informing future research and clinical care.




Conflict of Interest: The original research (published in Journal of Pediatrics) was partially supported by the 2012 Boston Children’s Hospital House Officer Development Award.

Response to: Rogol AD, Skakkebaek NE. Sperm retrieval in adolescent males with Klinefelter syndrome: medical and ethical issues. Transl Pediatr 2016;5:104-6.


  1. Rogol AD, Skakkebaek NE. Sperm retrieval in adolescent males with Klinefelter syndrome: medical and ethical issues. Transl Pediatr 2016;5:104-6. [Crossref] [PubMed]
  2. Nahata L, Yu RN, Paltiel HJ, et al. Sperm Retrieval in Adolescents and Young Adults with Klinefelter Syndrome: A Prospective, Pilot Study. J Pediatr 2016;170:260-5.e1-2. [Crossref] [PubMed]
  3. Nieschlag E, Ferlin A, Gravholt CH, et al. The Klinefelter syndrome: current management and research challenges. Andrology 2016;4:545-9. [Crossref] [PubMed]
  4. Mehta A, Bolyakov A, Roosma J, et al. Successful testicular sperm retrieval in adolescents with Klinefelter syndrome treated with at least 1 year of topical testosterone and aromatase inhibitor. Fertil Steril 2013;100:970-4. [Crossref] [PubMed]
  5. Maiburg MC, Hoppenbrouwers AC, van Stel HF, et al. Attitudes of Klinefelter men and their relatives towards TESE-ICSI. J Assist Reprod Genet 2011;28:809-14. [Crossref] [PubMed]
  6. Gies I, Tournaye H, De Schepper J. Attitudes of parents of Klinefelter boys and pediatricians towards neonatal screening and fertility preservation techniques in Klinefelter syndrome. Eur J Pediatr 2016;175:399-404. [Crossref] [PubMed]
  7. Rives N, Milazzo JP, Perdrix A, et al. The feasibility of fertility preservation in adolescents with Klinefelter syndrome. Hum Reprod 2013;28:1468-79. [Crossref] [PubMed]
  8. Close S, Fennoy I, Smaldone A, et al. Phenotype and Adverse Quality of Life in Boys with Klinefelter Syndrome. J Pediatr 2015;167:650-7. [Crossref] [PubMed]
  9. Plotton I, Giscard d'Estaing S, Cuzin B, et al. Preliminary results of a prospective study of testicular sperm extraction in young versus adult patients with nonmosaic 47,XXY Klinefelter syndrome. J Clin Endocrinol Metab 2015;100:961-7. [Crossref] [PubMed]
  10. Rohayem J, Fricke R, Czeloth K, et al. Age and markers of Leydig cell function, but not of Sertoli cell function predict the success of sperm retrieval in adolescents and adults with Klinefelter's syndrome. Andrology 2015;3:868-75. [Crossref] [PubMed]
  11. Gies I, Oates R, De Schepper J, et al. Testicular biopsy and cryopreservation for fertility preservation of prepubertal boys with Klinefelter syndrome: a pro/con debate. Fertil Steril 2016;105:249-55. [Crossref] [PubMed]
Cite this article as: Nahata L, Yu RN, Cohen LE. Klinefelter syndrome: fertility considerations and gaps in knowledge. Transl Pediatr 2016;5(3):183-184. doi: 10.21037/tp.2016.06.06