Short-term adverse effects of testosterone used for priming in prepubertal boys before growth hormone stimulation test

Introduction

The recommendation of priming with sex steroids in children before growth hormone (GH) provocative tests has changed in the recent years. In 2000, there was no consensus on the use of priming [1], whereas, in 2016, the updated guidelines of the Pediatric Endocrine Society recommended priming with sex steroids [2]. The German Society for Paediatric Endocrinology and Diabetology had already recommended priming in 2008 [3]. However, there are still some controversies. The guidelines of the Pediatric Endocrine Society limited priming to prepubertal girls >10 years and to prepubertal boys >11 years, whereas in Germany the ages for priming are ≥8 years for prepubertal girls and ≥10 years for prepubertal boys. According to Lazar and Phillip from Israel, priming should not be routinely performed in every peripubertal child undergoing GH evaluation but considered only in adolescents with pubertal delay, i.e. girls >11.5–12 years and boys >13–13.5 years [4]. The guidelines of the Paediatric Endocrine Society suggested giving β-estradiol orally to both boys and girls on two evenings preceding the test. The use of intramuscular (i.m.) testosterone (50–100 mg of a depot formulation administered 1 week before the test) was suggested as an alternative option [2], whereas, according to the German guidelines, boys should be primed with i.m. testosterone (50 mg testosterone enanthate) 1 week prior to the GH test [3]. Moreover, a study from the UK showed differences not only in the testosterone dosages but also in the testosterone preparation and the time between priming and the GH test [5].

Interestingly, there has been no discussion on the safety of this procedure. To date, only little data have been available on the possible side effects of priming with testosterone. Thus, the aim of our study was to evaluate the outcome in prepubertal boys primed with i.m. testosterone before GH axis testing and to analyze whether the applied dose or the achieved serum testosterone level after priming could be related to side effects.

Patients and methods

We studied a cohort of 188 prepubertal short-statured boys (mean age±SD; 11.4±1.25 years) with suspected GH deficiency. All boys were ≥10 years old.

Priming was performed by i.m. injection of a depot testosterone formulation (testosterone enanthate 250 mg/mL) 7 days before the GH stimulation test. The testosterone injections were performed by a home pediatrician or a medical practitioner. Between 2009 and 2010, we used a testosterone dose of 125 mg (n=51), and since 2011, all boys have been primed with a dose of 50 mg testosterone (n=136). One boy accidentally received 250 mg testosterone. At the time of the GH test, serum testosterone levels were measured in a cohort of 99 boys, among them four boys with reported side effects. Testosterone was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in our laboratory [SI units: ng/mL×3.47=nmol/L]. Informed written consent was given by the patients’ parents.

Results

The outcome in 188 prepubertal boys after priming with testosterone was analyzed. Only five patients showed adverse side effects (Table 1). The boy who was accidentally primed with 250 mg testosterone did not show any adverse side effect. Thus, the calculated overall adverse side effect rate after priming with testosterone was 2.7% in our cohort.

Discussion

The aim of our study was to evaluate the outcome of prepubertal boys primed with a single i.m. testosterone dosage before GH axis testing. The present study shows that there is a small risk of side effects for prepubertal boys. Generally, testosterone therapy is regarded as safe in children particularly when used in boys with hypogonadism. However, it is well known that adverse side effects might occur after high-dose testosterone application, but the reported data are not consistent.

In boys with excessively tall stature, who were treated with high doses of testosterone (500–1000 mg/month) for reduction of final height [6, 7], the most prevalent adverse side effect was acne [8, 9], but aggressive behavior and troublesome erections have also been reported [10].

Priapism is a prolonged and often painful penile erection lasting >4 h. There are three widely accepted types of priapism: (1) low-flow or ischemic priapism when blood gets trapped in the erection chambers, (2) stuttering priapism, recurrent, self-limiting prolonged erections and (3) high-flow or non-ischemic priapism when the blood flow from the penis is prevented usually due to trauma [11]. One of the most feared side effects of testosterone therapy is low-flow priapism which is often associated with devastating complications. In patients with sickle cell disease (SCD), there is a significant concern for these sequelae [12, 13]. However, it has been reported that the risk of priapism was not higher after treatment with a high dose i.m. testosterone undecanoate in SCD patients with hypogonadism [14]. On the contrary, Donaldson et al. [12] described a boy with SCD at the age of 14.7 years who received i.m. testosterone (0.6 mL Sustanon 250^®, Organon Laboratories Limited, Hertfordshire, UK) for priming prior to GH testing. Three days after the injection, he presented with a prolonged painful nocturnal erection. Ichioka et al. [15] reported on a low-flow priapism in a patient with Klinefelter syndrome within 12 days after an accidental high dose of 500 mg depot testosterone. Zargooshi et al. [16] reported low-flow priapism in a patient with hypogonadism starting 12 h after the application of 500 mg testosterone. A painful erection was reported in a 15-year-old boy with constitutional delay of growth and puberty (CDGP) after 250 mg depot testosterone [12]. Thus, it was speculated that the appearance of side effects might be related to the high testosterone dosage.

However, there are also case reports in the literature on side effects after low-dose testosterone replacement therapy performed in boys and men with hypogonadism and in boys with CDGP [12, 15, 16, 17, 18]. Arrigo et al. [19] reported a 14-year-old boy who had suffered from high-flow priapism after the 2nd monthly injection of 25 mg depot testosterone. Madrid Garcia et al. [18] found a 14-year-old boy with CDGP with priapism after administration of 100 mg testosterone which required the punction-aspiration of the corpora cavernosa. Shergill et al. [17] reported an 18-year-old patient with Kallmann’s syndrome who developed low-flow priapism 10 days after the first injection of 100 mg testosterone.

We cannot finally evaluate the symptom of testicular pain. Testicular pain has a number of possible causes, e.g. testicular torsion or orchitis but the cause cannot always be identified. Our data show that priapism and testicular pain might also occur in prepubertal boys who received a single testosterone dosage of either 50 mg or 125 mg for priming prior to GH testing. The injected testosterone dose was slightly higher in the two boys with severe priapism with a need for urologic intervention than in the boys with self-limiting stuttering priapism or testicular pain. One could speculate that the adverse effects are due to a sudden exuberant rise of the serum testosterone level. However, the serum testosterone levels in the patients with side effects were in the range of the testosterone levels in the boys without any side effects.

Conclusions

Parents and patients should be informed that the overall side effect rate is low after a single i.m. administration of testosterone for priming before GH testing. However, if side effects such as priapism and/or testicular pain occur, the children should be promptly presented to an urologist.