Clinical Endocrinology (2014) 80, 155158

doi: 10.1111/cen.12160

LETTERS TO THE EDITOR

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 prole 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 deciency (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 esteried testosterone (e.g. Sustanon, Bayer Schering Pharma AG, Berlin, Germany), oral testosterone undecanoate (oTU), hCG FSH sc injections and pulsatile sc GnRH.1 None of these products are specically designed or licensed for induction of puberty, and the oral and short-acting IM-esteried testosterone preparations are associated with major extraphysiological serum testosterone excursions and marked peaktrough difference.2 Expert reviews on pubertal induction tend to focus on suspected constitutional delay in younger teenagers,3 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 signicant 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 proles that approximate more closely to normal male physiology (albeit still with some peaktrough effect in TU).2 Testosterone transdermal gels have entered paediatric practice on the basis of satisfactory patient and physician experiences, with little published data1; 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 in4; IM TU administered only after 3 months pretreatment with oTU in5). However, it does offer signicant advantages in terms of smoother pharmacokinetics, and adherence can be optimized by combining monitoring and dose
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administration into a single visit. Prompted by rm 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 deciency. Age at presentation (mean 376 years; range 173578), clinical features and exclusion of broader hypopituitarism already pinpointed six as having IHH, for example, Kallmanns 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 48 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 34 months, guided by preinjection trough bloods, patient availability and, where possible, clinical assessments (amounting to mean 39 g/year). Four men presented in mature adult life (range 384578) 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 091 years (range 051104). However, we have satisfactory follow-up data (not presented here) extending 4 and 6 years from rst treatment for patents 1 and 4, both of whom originally presented in their 6th decade.4 The mean interval between TU injections was 1324 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 signicantly longer than the 12-week standard suggested by the product datasheet. 155

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Table 1. Baseline patient characteristics Provisional diagnosis KS KS KS KS nIHH nIHH/CDP nIHH Age at treatment initiation (years) 508 384 195 578 229 173 565 Height (m) 170 182 16 172 170 153 187 BMI (kg/m2) 30 254 192 225 245 164 272 Tanner stage (G.P.A) 331 332 322 222 332 221 222 LH (U/l) <10 <05 <05 <10 <10 24 <05 FSH (U/l) 11 05 11 <10 <10 20 <05 Testo (nM) 10 <10 <10 <10 <10 34 <10 f-Testo (pM) 160 <240 <70 <13 <22 31 <15 Hb (g/dl) 138 141 132 120 131 143 99 Hct (%) 429 411 376 376 390 413 303

Patient 1 2 3 4 5 6 7

Mean TV (ml) 10 <40 10 (R = undescended) 20 10 40 25

Table 2. Longitudinal response to treatment Baseline (n = 7) n/a 0 0 0 <10 (<1034)* 16 (<731)* 115 (99143) 385 (303429) Pre-2nd TU 1g (n = 7) 121 (718) 0 0 0 95 (39175) 172 (58319) 129 (n = 2) 390 (n = 2) Pre-3rd TU 1g (n = 7) 137 (917) 0 0 1 101 (61165) 221 (110354) 146 (143150) 437 (425452) Pre-4th TU 1g (n = 6) 138 (1217) 0 0 6 148 (98215) 347 (187549) 154 (14816) 454 (43947) Pre-5th TU 1g (n = 5) 134 (1118) 0 0 7 150 (93208) 363 (186532) 151 (137158) 461 (409515)

Means for Injection interval (weeks) n = TV >5 ml n = LH or FSH >20 IU/l n = reached Tanner 553 Testo (nM) f-Testo (pM) Hb (g/dl) Hct (%) *Median baseline value.

All patients had completed pubertal development by around a year from treatment initiation. As expected, during the specic time frame of this study (up to and including the 5th TU injection), none of these men entered endogenous gonadotrophin-driven puberty evidenced by increasing LH and FSH levels at preinjection trough or by testis enlargement (>5 ml). The sole patient (no. 6) with baseline phenotype compatible with CDP was lost to follow up just under 2 years from initial presentation, so we were unable to assign him a denitive diagnostic outcome. All seven patients completed full pubertal development without physical, psychological, biochemical or haematological adverse effects. IM TUs longer duration of action, and thus a reduced frequency of administration as compared to conventional testosterone esters, was appreciated by the patients and contributed to excellent adherence to testosterone replacement therapy during this key period in their lives. These data conrm preliminary ndings (reported in4) that IM TU is a safe and effective treatment for the initiation of puberty in males aged 17+ years and should help allay the (unfounded) anxieties of some clinicians in respect of inducing and maintaining puberty in very late-presenting apubertal men. Moreover, patients no. 1 and no. 4 (aged 508 and 578 years, respectively, at presentation and originally reported in4), for whom follow-up data extend 6 and 4 years, respectively,

exhibited striking improvements in bone mineral density (data shown in Appendix S3). However, our experience cannot be extrapolated to the treatment of younger teenagers with presumed CDP.

Conict of interest
There are no conicts of interest. Anjali Santhakumar*, Margaret Miller* and Richard Quinton*, *Endocrine Unit, Royal Victoria Inrmary, Newcastle-upon-Tyne Hospitals Foundation NHS Trust and Institute for Genetic Medicine, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, UK E-mail: richard.quinton@ncl.ac.uk doi: 10.1111/cen.12160

References
1 Raine, J.E., Donaldon, M.D.C., Gregory, J.W. et al. (2011) Practical Endocrinology and Diabetes in Children, 3rd edn. Wiley-Blackwell, Hoboken, NJ. 2 Yassin, A.A. & Haffejee, M. (2007) Testosterone depot injection in male hypogonadism: a critical appraisal. Clinical Interventions in Aging, 2, 577590.
2013 John Wiley & Sons Ltd Clinical Endocrinology (2014), 80, 155158

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3 Palmert, M.R. & Dunkel, L. (2012) Clinical practice: delayed puberty. The New England Journal of Medicine, 366, 443453. 4 Siddaramaiah, N., Miller, M. & Quinton, R. (2009) Use of testosterone undecanoate 1000 mg (Nebido) injections to induce puberty in 2 men with Kallmanns syndrome presenting in their 6th decade. Endocrine abstracts. 19: P39. 5 Giagulli, V.A., Triggiani, V., Carbone, M.D. et al. (2011) The role of long-acting parenteral testosterone undecanoate compound in the induction of secondary sexual characteristics in males with hypogonadotropic hypogonadism. The Journal of Sexual Medicine, 8, 34713478.

Supporting Information
Additional Supporting Information may be found in the online version of this article: Appendix S1. Modes of presentation and patient characteristics. Appendix S2. Source data for patient longitudinal response to treatment. Appendix S3. Longitudinal responses to treatment (PSA level & DEXA bone density).

There was a signicant (P < 0001) fall of HbA1c in the placebo arm similar to that seen in the pioglitazone arm. It would be informative to know what other factors affected HbA1c in the placebo arm (such as better compliance or increased physical activity) and whether same were applicable to pioglitazone arm. The authors screened 160 patients of whom 97 were excluded because their total testosterone was <12 nM or HbA1c > 75%, or BMI of >30 kg/m2, but only 54 patients were randomly assigned to receive either pioglitazone or placebo along with the existing glimepiride and metformin therapy. It would be informative if the authors could provide us with data regarding the missing 9 patients and the basis on which they were excluded from the study.

Acknowledgement
None to be declared.

Declaration by authors
No potential conicts of interests, all authors contributed equally to the manuscript, no one with a contribution has been left out.

Comments on Effect of pioglitazone on testosterone in eugonadal men with type 2 diabetes mellitus: a randomized double-blind placebo controlled study
It was interesting to read the article by Sridhar et al.1 which suggested that pioglitazone therapy signicantly decreases total, free and bioavailable testosterone in eugonadal men with type 2 diabetes mellitus. The authors also showed that the decrease in total testosterone was independent of any increase in SHBG, or change in body weight, body fat and HbA1c. Ozata et al.2 showed that metformin and a hypocaloric diet can signicantly reduce total testosterone levels in obese diabetic men. Decreased levels were not correlated with changes in waist and hip circumference, waist to hip ratio, BMI, levels of fasting blood glucose, leptin, SHBG or dehydroepiandrosterone sulphate in this diabetic group. This could be a potential confounder in the nal analysis of the study by Sridhar et al., and it would be interesting to know the mean doses of metformin used in the placebo group compared with the pioglitazone group. Metformin has been shown to reduce androgen levels in patients with polycystic ovarian syndrome.3 In a study by Fulghesu et al., the reduction in testosterone with metformin was dose dependent in patients with higher integrated insulin secretion. Metformin, by inhibiting hepatic glucose output, leads to a decrease in insulin concentration which also increases sex hormone binding globulin concentration.4 It would be important to know whether testosterone levels were assessed in the fasting state. Fasting levels of testosterone are important in view of the recent paper by Caronia et al.5 showing signicantly lower testosterone levels in diabetic patients after an oral glucose load.
2013 John Wiley & Sons Ltd Clinical Endocrinology (2014), 80, 155158

Guarantor
Dr. Manoj Kumar is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Manoj Kumar, Anubhav Thukral, Rajesh Jain, Sandeep Chaudhary, Satinath Mukherjee and Subhankar Chowdhury Department of Endocrinology, IPGME & R, Kolkata, India E-mail: manojkattu@gmail.com doi: 10.1111/cen.12214

References
1 Sridhar, S., Walia, R., Sachdeva, N. et al. (2013) Effect of pioglitazone on testosterone in eugonadal men with type 2 diabetes mellitus: a randomized double-blind placebo controlled study. Clinical Endocrinology, 78, 454459. 2 Ozata, M., Oktenli, C., Bingol, N. et al. (2001) The effects of metformin and diet on plasma testosterone and leptin levels in obese men. Obesity Research, 9, 662667. 3 Ehrmann, D.A. (2005) Polycystic ovary syndrome. New England Journal of Medicine 352, 12231236. 4 Fulghesu, A.M., Romualdi, D., Di Florio, C. et al. (2012) Is there a dose-response relationship of metformin treatment in patients with polycystic ovary syndrome? Results from a multicentric study. Human Reproduction, 27, 30573066. 5 Caronia, L.M., Dwyer, A.A., Hayden, D. et al. (2013) Abrupt decrease in serum testosterone levels after an oral glucose load in men: implications for screening for hypogonadism. Clinical Endocrinology, 78, 291296.