Pubertal induction in adult males with isolated hypogonadotropic hypogonadism using long‐acting intramuscular testosterone undecanoate 1‐g depot (Nebido®)

Dear Editors, Pubertal delay in males typically results from inadequate pulsatile secretion of hypothalamic gonadotrophin releasing hormone (GnRH), resulting in a biochemical profile of hypogonadotropic hypogonadism (low serum testosterone with low or inappropriately normal LH and FSH). In younger teenagers, this is most commonly due to constitutional delay (CDP), but the presence of organic gonadotrophin deficiency (e.g. idiopathic hypogonadotropic hypogonadism – IHH) is supported by a history of cryptorchidism, the presence of nonreproductive defects (anosmia, deafness, clefting, etc) and becomes exponentially more likely with increasing age at presentation. All forms of testosterone (exogenously administered or endogenously generated) are able to induce the development of normal secondary sexual characteristics in apubertal young males, including short-acting IM injections of esterified testosterone (e.g. Sustanon , Bayer Schering Pharma AG, Berlin, Germany), oral testosterone undecanoate (oTU), hCG FSH sc injections and pulsatile sc GnRH. None of these products are specifically designed or licensed for induction of puberty, and the oral and short-acting IM-esterified testosterone preparations are associated with major extraphysiological serum testosterone excursions and marked peak–trough difference. Expert reviews on pubertal induction tend to focus on suspected constitutional delay in younger teenagers, giving little guidance on managing older apubertal men. The latter tend to be of normal stature, but can be highly isolated socially, and so, the psychologically optimal tempo of physical change may be rather brisker. There are now significant availability issues in some older products. Short-acting injectables are anyway being increasingly replaced in adult endocrine practice by testosterone gels and by long-acting testosterone undecanoate IM injections (TU – Nebido , Bayer Schering Pharma AG, Berlin, Germany), due to better patient acceptability and serum testosterone profiles that approximate more closely to normal male physiology (albeit still with some peak–trough effect in TU). Testosterone transdermal gels have entered paediatric practice on the basis of satisfactory patient and physician experiences, with little published data; patient adherence between clinic visits can be hard to verify, unless consistently administered by the boys’ parents. Literature on the use of IM TU for induction of puberty is also limited (n = 2 patients in; IM TU administered only after 3 months pretreatment with oTU in). However, it does offer significant advantages in terms of smoother pharmacokinetics, and adherence can be optimized by combining monitoring and dose administration into a single visit. Prompted by firm patient preference in respect of chosen mode of androgen replacement, we switched several years ago to using IM TU for induction of puberty in older males. We retrospectively examined our experience with IM TU for pubertal induction in previously apubertal males aged 17+ with suspected IHH, focusing on (i) patient acceptability and tolerability, (ii) maintenance of physiologically appropriate haematocrit and trough serum testosterone levels and (iii) objective evidence of pubertal progression. Seven patients presented to a single consultant (RQ) between 2007 and 2011 with absent puberty and biochemical gonadotrophin deficiency. Age at presentation (mean 37 6 years; range 17 3–57 8), clinical features and exclusion of broader hypopituitarism already pinpointed six as having IHH, for example, Kallmann’s syndrome. Baseline and longitudinal data were recorded for weight, height, BMI, testis volume, pubertal staging (Tanner), phenotypic defects, serum total and calculated free testosterone, serum FSH and LH, haemoglobin and haematocrit. Treatment initiation scheme for hypogonadal males is classically with two TU injections spaced 6 weeks apart, with subsequent doses given every 12 weeks (amounting to 4 8 g/year). However, to elicit a less steep rise in serum testosterone from very low baseline, we did not routinely administer the ‘recommended’ 6-week ‘booster dose’; instead, administering IM TU approximately every 3–4 months, guided by preinjection trough bloods, patient availability and, where possible, clinical assessments (amounting to mean 3 9 g/year). Four men presented in mature adult life (range 38 4–57 8) and were externally apubertal, despite case records indicating some prior androgen exposure in two (see Appendix S1 for case vignettes). A common theme was reluctance to engage with the doctors and fear of being considered as ‘freaks’. We therefore adopted a ‘light touch’ approach, aiming to minimize clinic visits and intimate examinations, and with the principal point of care being a highly experienced endocrine nurse, who liaised with patients and primary care in respect of optimal TU injection intervals. Mean duration of treatment with TU over the period of observation (up to injection number 5) was 0 91 years (range 0 51–1 04). However, we have satisfactory follow-up data (not presented here) extending 4 and 6 years from first treatment for patents 1 and 4, both of whom originally presented in their 6th decade. The mean interval between TU injections was 13 24 weeks (data summarized in Tables 1 and 2; source data given in Appendix S2). No patients experienced adverse physical or psychological effects with TU, with the exception of rapid-onset male-pattern baldness in no. 1. Most dose intervals were significantly longer than the 12-week standard suggested by the product datasheet.