In earlier years, patients with KS were thought to have lifelong infertility. Due to advances in technology, it is now well established that these individuals can have isolated foci of spermatogenesis in the testis, and when sperm are extracted and injected into an egg, KS patients can conceive a biological child (Aksglaede and Juul 2013). Management now focuses on preserving fertility, but there is debate about how best to accomplish this goal as there have been no good controlled studies of adolescent males with KS. The choice boils down to one of three options: expectantly manage until the patient reaches adulthood and desires fertility, initiate medical treatment in adolescence and defer invasive biopsy until fertility is desired, or biopsy in adolescence with cryopreservation of sperm for future use.

Once the clinical features of KS are observed in an adolescent and the diagnosis is confirmed by karyotype, the question to be answered is whether the hypogonadism is symptomatic. The symptoms of low testosterone include fatigue, difficulty gaining muscle mass, trouble concentrating, and delayed secondary sex characteristics. A serum total testosterone level should be measured, and if it is less than 300 ng/dL on a morning blood draw, the diagnosis of male hypogonadism can be made, and the patient can begin testosterone supplementation therapy. The immediate goals for testosterone therapy are to promote secondary sex characteristics and stimulate linear growth, bone development, and muscle bulk. Long-term goals include possible augmentation of the disease process so that the cardiovascular, metabolic, and psychosocial features are less severe. Research has been published which recommends hormone therapy in adolescents with KS; however, there have been no controlled studies to determine the effect of testosterone supplementation on the progression of puberty (Bojesen and Gravholt 2007, Rogol and Tartaglia 2010). The method of application and dose of testosterone should be discussed with the patient, combining the clinician’s expertise and patient preference. Testosterone supplementation has side effects, as does any medication, and these should be discussed with the patient; however, the potential benefit of initiating early therapy seems to outweigh the risk of adverse effects. The particular side effect of exogenous testosterone administration of concern in a patient with KS is inhibition of already low testicular function, specifically spermatogenesis. Some cite this as an argument against administering testosterone therapy, since the effect on fertility is important to consider in this disorder (de Souza and Hallak 2011). In fact, a history of testosterone therapy is associated with a decreased sperm retrieval rate during microdissection testicular sperm extraction (TESE) in the general male population (Schiff et al. 2005, Ramasamy et al. 2009). However, men without KS who received human chorionic gonadotropin (hCG) in addition to testosterone therapy had no difference in semen parameters between their initial semen samples and samples obtained after 1 year of therapy (Hsieh et al. 2013). HCG is a luteinizing hormone (LH) analog and stimulates endogenous testosterone production and other testicular functions (Coviello et al. 2005). The drug is generally well tolerated and has few side effects. The drawbacks of using hCG are that it is expensive and it requires injections in addition to administration of testosterone. Thus, for an adolescent with KS and symptomatic hypogonadism, it is best to initiate testosterone supplementation therapy and hCG to prevent the comorbidities of the disorder while preserving testicular function. Clomiphene and anastrazole are other adjuncts to testosterone supplementation for preserving fertility and endogenous testicular function, but they have not been thoroughly studied for this specific use (Moskovic et al. 2012, Burnett-Bowie et al. 2008). Some experts still argue against initiating any therapy before fertility is desired, thus additional clinical trials are required to determine the best management plan for adolescent patients with KS.

Cryopreservation should be considered in this population only when mature and viable sperm are found on an ejaculated specimen. Obtaining mature sperm or germ cells by TESE followed by cryopreservation is not recommended for the adolescent with KS for several reasons. Since sperm retrieval rates are relatively high in KS adults, at least equal to those of men with other causes of nonobstructive azoospermia, there is no advantage in performing the procedure on an adolescent, especially since he may be unsure of desiring fertility in the future (Vernaeve et al. 2004). Moreover, the procedure could have a negative impact on testicular function. In a KS patient, the chance of finding viable germ cells in normal seminiferous tubules is low, and multiple biopsies would likely be required. After any TESE, serum testosterone levels decrease and do not reach preprocedure levels even a year later (Okada et al. 2004). In addition, the seminiferous tubule volume decreases in the testicular parenchyma around the biopsy site, and the number of germ cells per tubule decreases (Tash and Schlegel 2001).