Klinefelter syndrome: An argument for early aggressive hormonal and fertility management

15 08 2012

To the Editor:

We would like to thank Drs. Mehta and Paduch for their fine article (1). The aim of their systematic review/meta-analysis was to investigate the effect of early hormone replacement therapy (HT) on sperm retrieval rates in patients with Klinefelter syndrome (KS). In this article the authors reported that early HT is recommended in patients with KS, but its effect on fertility potential has not been studied in detail. Cryopreservation of sperm containing semen or testicular tissue from a significant proportion of affected adolescents should be considered to maximize future fertility potential. We greatly appreciate this paper, but there are some issues that should be highlighted.

KS is the most common form of male hypogonadism with a varying degree of androgen deficiency; testosterone replacement therapy (TRT) is widely used to prevent the symptoms and sequels of androgen deficiency. However, its effect on fertility potential is still unknown. There were no randomized controlled trials that evaluated the effect of TRT on sperm retrieval or reproductive outcomes in KS. Exogenous testosterone can suppress sperm function irreversibly (2). During spermatogenesis, TRT causes a marked inhibition of spermatogonial maturation, and thus, some studies recommend freezing semen samples before the initiation of testosterone supplementation (2-4). These data also recommend the cryopreservation of sperm containing either semen or testicular tissue. It was reported that early to mid-puberty may be the best time for sperm retrieval when there is a brief increase in testicular size, and serum hormone concentrations are relatively within normal range. However, the optimal time for this procedure has not been established so far. In fact, testicular volume, serum FSH, LH, testosterone, inhibin levels, testicular ultrasonography, and testicular histology are not predictive factors for testicular sperm extraction (TESE) (3). New diagnostic and imaging tests may aid in timing surgical and hormonal interventions in the future.

There are also some problems during sperm retrieval in these patients. The children and their families should be counseled because these patients may need a surgical procedure that has only a 50% chance of recovering any sperm (6). Unsuccessful sperm recovery after TESE has a negative emotional impact. These patients should also undergo counseling with genetics, because aneuploidy rates are higher and the patient may need preimplantation genetic screening, chorionic villus sampling, or amniocentesis (5). Moreover, chromosomal abnormalities are also increased even when they have normal karyotype (6). These future problems must be discussed with the patient and his parents carefully. The role of parents in medical decisions is usually significant and must be considered.

Fatma Ferda Verit, M.D.
Suleymaniye Maternity, Research and Training Hospital, Department of Obstetrics and Gynecology, Infertility Research & Treatment Center
Istanbul, Turkey

Ayhan Verit, M.D.
Fatih Sultan Mehmet, Research and Training Hospital, Department of Urology
Istanbul, Turkey

References

1. Mehta A, Paduch DA. Klinefelter syndrome: an argument for early aggressive hormonal and fertility management. Fertil Steril 2012;98:274-83.

2. Gies I, De Schepper J, Van Saen D, Anckaert E, Goossens E, Tournaye H. Failure of a combined clinical- and hormonal-based strategy to detect early spermatogenesis and retrieve spermatogonial stem cells in 47,XXY boys by single testicular biopsy. Hum Reprod 2012;27:998-1004.

3. Wikström AM, Dunkel L. Testicular function in Klinefelter syndrome. Horm Res 2008;69:317-26.

4. Wikström AM, Raivio T, Hadziselimovic F, Wikström S, Tuuri T, Dunkel L. Klinefelter syndrome in adolescence: onset of puberty is associated with accelerated germ cell depletion. J Clin Endocrinol Metab 2004;89:2263–70.

5. Vialard F, Bailly M, Bouazzi H, Albert M, Pont JC, Mendes V et al. The High frequency of sperm aneuploidy in Klinefelter patients and in non-obstructive azoospermia is due to meiotic errors in euploid spermatocytes. J Androl 2012 Apr 5[Epub ahead of print].

6. Fullerton G, Hamilton M, Maheshwari A. Should non-mosaic Klinefelter syndrome men be labeled as infertile in 2009? Human Reprod 2010;25:588-97.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2012.08.031

The authors respond:

We are in agreement with the observations made by Drs. Verit and Verit. While the use of early hormonal therapy has been recommended for Klinefelter syndrome (KS) patients by several investigators and clinicians, our systematic review of the literature demonstrates a lack of prospective, randomized controlled trials that evaluate the effect of testosterone replacement therapy (TRT) on fertility and reproductive outcomes (1). No clinical predictors of testicular function have been definitively identified to date. Further investigation is certainly needed on this topic.

The administration of exogenous testosterone may suppress LH and FSH, thereby suppressing spermatogenic function, and certainly has the potential to do so irreversibly. However, we are unaware of any studies demonstrating such irreversible suppression of spermatogenic function. On the contrary, in our experience to date, TRT in adolescents with KS has been associated with improvement in physical growth and development, without any major reported adverse consequences. Additionally, we have successfully retrieved sperm via TESE in 5 KS adolescents maintained on TRT for >6 months. Although anecdotal, this observation suggests that the suppression of spermatogenesis resulting from TRT may not be complete or universal in all patients with KS. The degree of suppression of spermatogenesis may also vary with the duration of TRT, and formulation and dose used.

Undergoing sperm retrieval can be emotionally and physically challenging for adolescents with KS, especially in light of the potential chances of a successful outcome. Appropriate consultation with medical genetics, psychological counseling, and parental involvement is, of course, essential before any surgical decision-making. In order to maximize sperm retrieval rates, however, we recommend microsurgical testicular sperm extraction rather than one or more random testicular biopsies, which, though less invasive, are also less likely to be successful in the setting of compromised pre-existing testicular function (2).

Akanksha Mehta, M.D. and Darius A. Paduch, M.D.
Department of Urology, Weill Cornell Medical College, New York, NY

References

1. Mehta A, Paduch DA. Klinefelter syndrome: an argument for early aggressive hormonal and fertility management. Fertil Steril 2012;98:274-83.

2. Gies I, De Schepper J, Van Saen D, Anckaert E, Goossens E, Tournaye H. Failure of a combined clinical- and hormonal-based strategy to detect early spermatogenesis and retrieve spermatogonial stem cells in 47,XXY boys by single testicular biopsy. Hum Reprod 2012;27:998-1004.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2012.08.032

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