J Pediatr Endocrinol Metab 2018; 31(1): 21–24

Andrea Albrecht, Theresa Penger, Michaela Marx, Karin Hirsch and Helmuth G. Dörr* Short-term adverse effects of testosterone used for priming in prepubertal boys before growth hormone stimulation test https://doi.org/10.1515/jpem-2017-0280 such as priapism and testicular pain. However, the overall Received July 17, 2017; accepted October 31, 2017; previously side effect rate is low. We found no correlation between ­published online December 4, 2017 the outcome and the testosterone dose used and/or the Abstract level of serum testosterone. Keywords: growth hormone (GH) test; prepubertal boys; Background: Despite the fact that priming with sex ster- priming; testosterone. oids in prepubertal children before growth hormone (GH) provocative tests is recommended, there is an ongoing controversial discussion about the appropriate age of the children, the drug used for priming, the dose and the Introduction period between priming and the GH test. Interestingly, there is no discussion on the safety of this procedure. To The recommendation of priming with sex steroids in chil- date, only little data have been available on the possible dren before growth hormone (GH) provocative tests has side effects of priming with testosterone. changed in the recent years. In 2000, there was no consen- Methods: We analyzed the outcome in 188 short-statured sus on the use of priming [1], whereas, in 2016, the updated prepubertal boys who had been primed with testosterone guidelines of the Pediatric Endocrine Society recommended enanthate (n = 136: 50 mg; n = 51: 125 mg, and accidentally priming with sex steroids [2]. The German Society for Pae- one boy with 250 mg) 7 days prior to the GH test. Serum diatric Endocrinology and Diabetology had already recom- testosterone levels were measured on the day of the GH mended priming in 2008 [3]. However, there are still some test in 99 boys. controversies. The guidelines of the Pediatric Endocrine Results: Overall, only five boys developed adverse side Society limited priming to prepubertal girls >10 years and effects. Two boys (dose 125 mg) showed severe low-flow to prepubertal boys >11 years, whereas in Germany the ages priapism and had to undergo decompression of the corpora for priming are ≥8 years for prepubertal girls and ≥10 years cavernosa. One boy suffered from self-limiting priapism for prepubertal boys. According to Lazar and Phillip from and testicular pain (dose 50 mg). Two patients reported Israel, priming should not be routinely performed in every testicular pain (each dose 50 mg). The single patient with peripubertal child undergoing GH evaluation but consid- 250 mg testosterone did not show any adverse effects. The ered only in adolescents with pubertal delay, i.e. girls >11.5– total side effect rate was 2.7%. The serum testosterone 12 years and boys >13–13.5 years [4]. The guidelines of the levels of the boys with side effects were not different from Paediatric Endocrine Society suggested giving β-estradiol the testosterone levels of the boys without any side effects. orally to both boys and girls on two evenings preced- Conclusions: Parents and patients should be informed ing the test. The use of intramuscular (i.m.) testosterone about the possible side effects of priming with 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 enan- *Corresponding author: Prof. Dr. med. Helmuth G. Dörr, Division of Paediatric Endocrinology, Department of Paediatrics, University thate) 1 week prior to the GH test [3]. Moreover, a study from Hospital, Friedrich Alexander-Universität Erlangen-Nürnberg, the UK showed differences not only in the testosterone Loschgestr. 15, 91054 Erlangen, Germany, Phone: +49 (0) 9131-853- dosages but also in the testosterone preparation and the 3732, E-mail: [email protected] time between priming and the GH test [5]. Andrea Albrecht, Theresa Penger and Michaela Marx: Paediatric Interestingly, there has been no discussion on the Endocrinology, Department of Paediatrics and Adolescent Medicine, University Hospital of Erlangen, Erlangen, Germany safety of this procedure. To date, only little data have Karin Hirsch: Paediatric Urology, Department of Urology, University been available on the possible side effects of priming with Hospital of Erlangen, Erlangen, Germany testosterone. Thus, the aim of our study was to evaluate 22 Albrecht et al.: Priming with testosterone the outcome in prepubertal boys primed with i.m. tes- testosterone. When asked, the boys denied any sexual tosterone before GH axis testing and to analyze whether manipulation, e.g. masturbation. But we cannot exclude the applied dose or the achieved serum testosterone level this fact. In both cases, conservative treatment did not after priming could be related to side effects. lead to detumescence. Finally, decompression of the cav- ernous bodies by blood aspiration had to be performed in the Division of Paediatric Urology. After the intervention, Patients and methods therapy with etilefrin hydrochloride for 1 week was initi- ated. Hematologic and toxicologic reasons for priapism We studied a cohort of 188 prepubertal short-statured boys (mean were excluded. The testosterone levels at the time of the age ± SD; 11.4 ± 1.25 years) with suspected GH deficiency. All boys GH tests ranged between 4.01 and 4.03 ng/mL. Testoster- were ≥10 years old. one levels at the time of the manifestation of the priapism Priming was performed by i.m. injection of a depot testosterone formulation (testosterone enanthate 250 mg/mL) 7 days before the were not measured. 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 Patient 3 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 A 10-year-old boy, primed with 50 mg testosterone i.m., test, serum testosterone levels were measured in a cohort of 99 boys, suffered from stuttering priapism and testicular pain among them four boys with reported side effects. Testosterone was starting 5 days after the injection. The symptoms were measured by liquid chromatography-tandem mass spectrometry (LC- self-limiting within a few days so no further urologic diag- MS/MS) in our laboratory [SI units: ng/mL × 3.47 = nmol/L]. Informed written consent was given by the patients’ parents. nostics or therapy were necessary. The serum testosterone level at the time of the GH test was 7.97 ng/mL.

Results Patients 4 + 5

The outcome in 188 prepubertal boys after priming with tes- Two boys aged 10 years who had been primed with 50 mg tosterone was analyzed. Only five patients showed adverse testosterone i.m. reported testicular pain without pria- side effects (Table 1). The boy who was accidentally primed pism. The testosterone level of patient 4 was 26.3 ng/mL, with 250 mg testosterone did not show any adverse side the testosterone level of patient 5 was not available. effect. Thus, the calculated overall adverse side effect rate after priming with testosterone was 2.7% in our cohort. Serum testosterone levels

Case reports Serum testosterone levels of 95 boys (n = 87: primed with 50 mg; n = 8: primed with 125 mg) without side effects Patients 1 + 2 ranged from 0.38 to 46.1 ng/mL (mean ± SD: 9.8 ± 7.7, median: 6.2). There was no significant difference in the Two boys (twins aged 12 years) developed severe low- testosterone levels (mean ± SD) between the two doses flow priapism 2 weeks after the i.m. injection of 125 mg (50 mg: 9.9 ± 7.8; 125 mg: 10.6 ± 5.5). The testosterone levels in four of the five boys with side effects (missed: n = 1) ranged from 4.0 to 26.3 ng/mL and were within the range Table 1: Serum testosterone levels (ng/mL) in boys with reported of the boys without side effects (Table 1). The testosterone adverse side effects after priming with depot testosterone. level of the boy who was accidentally primed with 250 mg testosterone was 18.2 ng/mL. There was no association Side effect Dose, mg Testosteronea between adverse effects and the serum testosterone levels. Patient 1 Low flow priapism 125 4.01 Patient 2 Low flow priapism 125 4.31 Patient 3 Stuttering priapism + 50 7.97 testicular pain Discussion Patient 4 Testicular pain 50 26.3 Patient 5 Testicular pain 50 Not available The aim of our study was to evaluate the outcome of prepu- ang/mL × 3.47 = nmol/L. bertal boys primed with a single i.m. testosterone dosage Albrecht et al.: Priming with testosterone 23 before GH axis testing. The present study shows that there of the corpora cavernosa. Shergill et al. [17] reported an is a small risk of side effects for prepubertal boys. Gener- 18-year-old patient with Kallmann’s syndrome who devel- ally, testosterone therapy is regarded as safe in children oped low-flow priapism 10 days after the first injection of particularly when used in boys with hypogonadism. 100 mg testosterone. However, it is well known that adverse side effects might We cannot finally evaluate the symptom of testicular occur after high-dose testosterone application, but the pain. Testicular pain has a number of possible causes, e.g. reported data are not consistent. testicular torsion or orchitis but the cause cannot always In boys with excessively tall stature, who were treated be identified. Our data show that priapism and testicular with high doses of testosterone (500–1000 mg/month) for pain might also occur in prepubertal boys who received reduction of final height [6, 7], the most prevalent adverse a single testosterone dosage of either 50 mg or 125 mg for side effect was acne [8, 9], but aggressive behavior and priming prior to GH testing. The injected testosterone dose troublesome erections have also been reported [10]. was slightly higher in the two boys with severe priapism Priapism is a prolonged and often painful penile erec- with a need for urologic intervention than in the boys tion lasting >4 h. There are three widely accepted types of with self-limiting stuttering priapism or testicular pain. priapism: (1) low-flow or ischemic priapism when blood One could speculate that the adverse effects are due to gets trapped in the erection chambers, (2) stuttering pria- a sudden exuberant rise of the serum testosterone level. pism, recurrent, self-limiting prolonged erections and (3) However, the serum testosterone levels in the patients high-flow or non-ischemic priapism when the blood flow with side effects were in the range of the testosterone from the penis is prevented usually due to trauma [11]. levels in the boys without any side effects. One of the most feared side effects of testosterone therapy is low-flow priapism which is often associated with devas- tating complications. In patients with sickle cell disease (SCD), there is a significant concern for these sequelae [12, Conclusions 13]. However, it has been reported that the risk of priapism was not higher after treatment with a high dose i.m. testos- Parents and patients should be informed that the overall terone undecanoate in SCD patients with hypogonadism side effect rate is low after a single i.m. administration of [14]. On the contrary, Donaldson et al. [12] described a testosterone for priming before GH testing. However, if boy with SCD at the age of 14.7 years who received i.m. side effects such as priapism and/or testicular pain occur, testosterone (0.6 mL Sustanon 250®, Organon Laborato- the children should be promptly presented to an urologist. ries Limited, Hertfordshire, UK) for priming prior to GH testing. Three days after the injection, he presented with Author contributions: All the authors have accepted a prolonged painful nocturnal erection. Ichioka et al. [15] responsibility for the entire content of this submitted reported on a low-flow priapism in a patient with Klinefel- manuscript and approved submission. ter syndrome within 12 days after an accidental high dose Research funding: None declared. of 500 mg depot testosterone. Zargooshi et al. [16] reported Employment or leadership: None declared. low-flow priapism in a patient with hypogonadism start- Honorarium: None declared. ing 12 h after the application of 500 mg testosterone. A Competing interests: The funding organization(s) played painful erection was reported in a 15-year-old boy with no role in the study design; in the collection, analysis, and constitutional delay of growth and puberty (CDGP) after interpretation of data; in the writing of the report; or in the 250 mg depot testosterone [12]. Thus, it was speculated decision to submit the report for publication. 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 References therapy performed in boys and men with hypogonadism and in boys with CDGP [12, 15–18]. Arrigo et al. [19] reported 1. Consensus guidelines for the diagnosis and treatment of growth a 14-year-old boy who had suffered from high-flow pria- hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society. J Clin pism after the 2nd monthly injection of 25 mg depot tes- Endocrinol Metab 2000;85:3990–3. tosterone. Madrid Garcia et al. [18] found a 14-year-old boy 2. Grimberg A, DiVall SA, Polychronakos C, Allen DB, Cohen LE, with CDGP with priapism after administration of 100 mg et al. 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