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Abstracts
Managing endocrine dysfunction following blast injury to the male external genitalia
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Department of Endocrinology and Diabetes, Northumbria and Newcastle NHS Trusts, University of Newcastle, MDHU Northallerton, UK 2 Department of Rheumatology and Rehabilitation, Defence Medical Rehabilitation Centre, Surrey, UK 3 Department of Endocrinology, Royal Victoria Infirmary, University of Newcastle, Newcastle upon Tyne, UK Correspondence to Lt Col David R Woods, Department of Endocrinology and Diabetes, Northumbria and Newcastle NHS Trusts, University of Newcastle, MDHU Northallerton, UK;
[email protected] Received 24 January 2013 Accepted 24 January 2013
ABSTRACT Blast injury to the external genitalia is associated with considerable morbidity, including the risk of primary hypogonadism due to insufficient testosterone. It is of the utmost importance that, prior to any testosterone replacement being commenced, serious consideration is given to sperm retrieval. The clinical and biochemical picture of hypogonadism allows a relatively straightforward diagnosis in most cases although it is important to be alert to the possibility of hypogonadism in the context of partial testicular tissue preservation. It is also prudent to consider the possibility of secondary hypogonadism especially in patients with chronic pain or those on opiate medication. Therapeutic options for testosterone replacement are diverse but relatively simple. This article aims to give guidance to the non-specialist in the consideration, diagnosis, and treatment of hypogonadism, with particular reference to blast injury of the external genitalia.
INTRODUCTION
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As discussed elsewhere in this supplement the improvised explosive device (IED) constitutes a major threat to the external genitalia. This article focuses on the endocrine consequences of such trauma: how to simply diagnose it, treat it and monitor progress. The article is intended to allow non-endocrinologists to detect, diagnose and instigate treatment for primary hypogonadism where appropriate. In cases of uncertainty discussion with endocrinology services is appropriate and the corresponding author and co-author Richard Quinton (0191 2336161) are both very happy to be contacted. It is beyond the scope of this article to discuss the psychosexual issues in relation to genital trauma, erectile function and hypogonadism.
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THE PHYSIOLOGY, FUNCTION AND MEASUREMENT OF TESTOSTERONE
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67 68 69 70 71
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David R Woods,1 R Phillip,2 R Quinton3
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To cite: Woods DR, Phillip R, Quinton R. J R Army Med Corps Published Online First: [ please include Day Month Year] doi:10.1136/jramc-2013000022
Testosterone is the principal androgen produced in the Leydig cells of the testis. In the post-pubertal male the main role of testosterone is in the maintenance of spermatogenesis, libido, erectile function, secondary sexual hair, the classic male secondary sex characteristics. Testosterone also has important roles in erthyrocytosis, conservation of bone density and lean muscle mass as well as in feelings of general wellbeing. There is a marked (up to 50%)1 diurnal variation in testosterone levels with an early morning peak which has relevance to the timing of assay requests which should be done on 0900 hrs specimens. A ‘normal’ testosterone depends on locally-derived laboratory references but generally will be somewhere in the region of 9.9–27.8 nmol/l; only 2–4%
Woods DR, et al. J R Army Med Corps 2013;0:1–4. doi:10.1136/jramc-2013-000022
of testosterone circulates freely and is therefore biologically active. The rest is bound to proteins, particularly albumin and sex hormone binding globulin (SHBG), which is of relevance in cases of diagnostic ambiguity and states that alter SHBG or albumin levels such as liver disease, alcohol, obesity, thyroid disorders and post-operational deployment (Woods and Quinton, unpublished observation). Two pituitary hormones are critical to normal testicular function: luteinizing hormone (LH) stimulates testosterone synthesis and secretion and follicle stimulating hormone (FSH) stimulates spermatogenesis in the Sertoli cells. Both hormones are controlled by pulses of gonadotropin releasing hormone (GnRH) from the hypothalamus. Testosterone secretion inhibits LH and FSH is inhibited by both testosterone and another protein secreted by the Sertoli cells, inhibin. Testosterone contributes to a classical feedback loop with the pituitary hormones LH and FSH. Therefore, by logical interpretation of a low testosterone in the presence of elevated FSH and LH it can be ascertained that the cause of the low testosterone is primary gonadal failure, which in the context of this article that is trauma to the external genitalia, and a low testosterone in the presence of an inappropriately normal or low LH and FSH suggests that the problem must lie more centrally (central or secondary hypogonadism).
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HOW TO MAKE A DIAGNOSIS OF HYPOGONADISM
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Hypogonadism is a clinical syndrome with symptoms such as erectile dysfunction, reduced libido and sweating (Box 1), possibly some signs (gynaecomastia and reduced secondary sexual hair) and biochemical evidence of testosterone deficiency. Hypogonadism may either be primary, due to testicular problems with testosterone production such as occur following trauma, mumps orchitis, with excess alcohol or in common chromosomal abnormalities such as Klinfelter’s syndrome, or secondary due to problems with the pituitary or hypothalamic hormones that drive testosterone production, such as occur with pituitary macroadenomas, prolactinomas, following cranial irradiation for childhood tumours or in genetic syndromes such as Kallmann’s syndrome. In the context of this article the aetiology is obviously traumatic with blast injury to the external genitalia leading to primary hypogonadism. However, it is important to highlight that in the military setting the clinician should remain alert to the relatively common causes of secondary hypogonadism that will be seen such as that associated with chronic pain, opiate use, head trauma or extreme exercise, stress or weight changes. In addition, it is also appreciated that
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1
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Abstracts 129
Box 1 Effects of reduced testosterone in post-pubertal male
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▸ ▸ ▸ ▸
134 135 136 137 138
▸ ▸ ▸ ▸ ▸ ▸ ▸
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Erectile dysfunction (ED) and reduced libido Depression and Fatigue Sweating Reduced secondary sexual hair-including reduced requirement to shave Gynaecomastia Reduced muscle mass Reduced bone mineral density-frank osteoporosis Increased adipose tissue Normocytic anaemia Impaired wound healing Thinning skin
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functional temporary hypothalamic hypogonadism may occur in relation to acute/chronic disease/stress, including situations such as military training.2 It is highly pertinent to the military setting that the reduction in testosterone that may occur during acute severe illness means a diagnosis should not usually be made in that setting. The diagnosis of primary hypogonadism is relatively straightforward in the clinical setting of blast injury to the perineum in that in the context of significant testicular injury a 0900 hrs testosterone with LH and FSH should always be requested. Biochemical confirmation of primary hypogonadism is demonstrated by a low 0900 hrs testosterone and an elevated LH and FSH. Secondary hypogonadism would be suggested by a low 0900 hrs testosterone and an inappropriately low or normal LH and FSH. Prior to committing an individual to lifelong testosterone replacement therapy (TRT), and in acknowledgement of the fact that testosterone assays can give variable results3 in addition to the significant intra-individual variation in testosterone4 as a bare minimum the 0900 hrs testosterone, LH and FSH should be repeated and be consistently low before a diagnosis is made. A guide to interpreting testosterone levels is given in Table 1. Primary hypogonadism can still be present following blast injury to the perineum in the presence of unilateral testicular loss and in cases of biochemical ambiguity it is very helpful to assay 0900 hrs SHBG and albumin. These measures, along with testosterone allow calculation of the bioavailable testosterone.
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Table 1 Interpretation of testosterone results
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Testosterone level (refer to local reference values)
181 182 183 184
12 nmol/l
190 191
Basic interpretation Highly supportive of hypogonadism Indeterminate, may warrant trial of treatment Highly likely to be normal
SHBG, Sex Hormone Binding Globulin.
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2
Bioavailable testosterone (when testosterone and SHBG reported in nmol/l and albumin as g/l) 5 nmol/l
Basic interpretation Definitely abnormal Indeterminate, may warrant trial of treatment Normal
As discussed above an elevated SHBG reduces the free, active testosterone and therefore the effective bioavailable testosterone is reduced. Bioavailable testosterone is a calculation of the free testosterone plus that loosely bound to albumin (which in this sense is considered ‘bioavailable’ as it readily dissociates from albumin). Some laboratories will calculate bioavailable testosterone automatically, alternatively websites such as http://www. issam.ch/freetesto.htm allow rapid calculation. Therefore in situations where the total testosterone is borderline, or where conditions exist that may affect SHBG, calculation of the bioavailable testosterone, or alternatively the free testosterone may help clarify a diagnosis. Free testosterone (normal range 215–760 pmol/l) may be calculated by the equation5:
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Calculated free testosterone p ¼ f ½ðSHBG T þ 23Þ2 þ ð92 TÞ ðSHBG T þ 23Þg=0:046:
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TESTOSTERONE REPLACEMENT THERAPY When and when not to prescribe
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Put simply, testosterone replacement therapy is usually indicated once hypogonadism has been diagnosed and it has been determined that there are no contraindications. In the setting of testicular trauma in a relatively young population there are however additional considerations, particular in relation to sperm retrieval. As alluded to above, high testosterone levels inhibit LH and FSH and if we consider the crucial role FSH has in driving spermatogenesis then it is easy to appreciate that once exogenous TRT has been administered the reduction in endogenous production of LH and FSH will consequently reduce the FSH drive for spermatogenesis. Trials of testosterone as a contraceptive have indicated that sperm counts may return to normal if therapy is withdrawn.6 However, in cases of testicular trauma this may not be the case since the testis is possibly going into progressive failure in which spermatogenesis may anyway cease. Further, there are no data as to whether recovery of sperm counts would occur following prolonged testosterone use and such withdrawal of treatment may have to be for a protracted period. In the setting of residual, viable testicular tissue where there is the prospect of sperm retrieval it is crucial therefore to delay TRT until the opportunity for sperm retrieval has been considered and undertaken prior to the commencement of therapy. Generally the aim of therapy is to induce and maintain secondary sex characteristics and to improve sexual function, sense of well-being, muscle mass and strength, and bone mineral density. Additional benefits are an increase in erythrocytosis (a normocytic anaemia may develop in prolonged hypogonadism), the resolution of symptoms of sweating and a reduction in fat mass. In the setting of the Defence Medical Rehabilitation Centre (DMRC), Headley Court it has also become apparent that effective TRT has a sigificant part in maximising the rehabilitation of individuals following testicular and multiple trauma. Generally, in our young military population, there are very few practical contra-indications to TRT but it is important that the clinician is aware and thus they are listed in Box 2.7 European and American guidelines7 8 recommend a rectal examination of the prostate in addition to assessment of Prostate Specific Antigen (PSA) at baseline, three months and then ‘according to evidence-based guidelines’ thereafter. There
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Box 2 Contra-indications to Testosterone Replacement Therapy
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Absolute contra-indications ▸ Prostate cancer or un-evaluated elevated PSA ▸ History of primary liver tumours ▸ Breast cancer ▸ Untreated prostatic hyperplasia causing bladder outlet obstruction Relative contra-indications ▸ Eryhtrocytosis (haematocrit, HCT, >0.5) ▸ Nephrotic syndrome ▸ Untreated severe Obstructive Sleep Apnoea Syndrome (may be exacerbated with testosterone) ▸ Uncontrolled heart failure (fluid retention may worsen with testosterone), but probably beneficial effect on cardiac function once medical control has been optimised.
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is very little evidence on which to base informed opinion regarding this and most UK endocrinologists adopt a more conservative and pragmatic approach with rectal examination
There are a plethora of TRT products available and it is important the prescribing clinician is aware of all the options so that the patient can make an informed choice. The therapeutic options are summarised in Table 2. Clinical experience of patients treated with TRT at DMRC, Headley Court following blast injury to the testicles has anecdotally found sustained success both in terms of appropriate biochemical replacement and patient satisfaction with depot intramuscular testosterone undecanoate (eg, Nebido1000 mg). Three brief case reports outlined in Table 3 illustrate the DMRC experience with depot testosterone. From a rehabilitation perspective depot preparations have other advantages over, for example, gel preparations. Gel preparations can be challenging for those with multiple injuries with manual dexterity issues, a lack of intact skin surface area for absorption and also have the added potential for the transfer of testosterone during patient handling and therapy in addition to difficulties in timing of water therapy. In long-term testosterone naïve subjects (for example those diagnosed with Klinfelter’s syndrome in their 50’s) it is appropriate to start with a gentle dose of testosterone and build up gradually. In the setting of acute traumatic hypogonadism
Table 2 Therapeutic options in testosterone replacement
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Preparation
Dosing interval
Comments
Intramuscular testosterone undecanoate (eg, Nebido1000 mg)
10–16 weeks. If rapid steady-state desired a second injection can be given 6 weeks after the first and then every 10–14 weeks.
Less painful if warmed to room temperature before injection and injected slowly. Generally provides a more durable and consistent testosterone level than testosterone esters. Adjust dose frequency according to pre-dose testosterone. If pre-dose levels are at upper end of normal range, consider extending duration between injections. Adjust dosing frequency based on subjective patient well-being and testosterone levels mid-way between doses. Generally found to result in testosterone levels above the reference range immediately following injection and below the reference range pre-dosing. Testosterone concentrations should be measured in the mornings, before the application of the gel. Can assess testosterone 1–2 weeks after started. Both Testogel and Testim preparations may be increased to maximum 100 mg testosterone/day.
291 292 293
Intramuscular testosterone esters (eg, Sustanon 250 mg)
2–4 weeks
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Testosterone gels (eg, 5 g of Testogel containing 50 mg Once daily, preferably in the morning. Apply thin layer of of testosterone or Testim, 5 g gel/50mg testosterone) gel on clean, dry, healthy skin for example, shoulders/ arms/abdomen and then allow to dry (3–5 mins) before dressing. Wash hands to avoid cross-contamination of others, and avoid shower or bath for 6 h. Avoid skin contact with others at application site (especially pregnant women and children). Tostran, 3 g gel/60 mg testosterone (3 g usual starting Once daily, preferably in the morning. Apply thin layer of dose), max. 80 mg (4 g gel) daily (Tostran gel is 20 mg gel on clean, dry, healthy skin of abdomen or both inner thighs-rotate sites daily. Allow to dry (3–5 mins) before testosterone per 1 g gel, one press of the canister dressing, wash hands to avoid cross-contamination of piston delivers 0.5 g gel, 10 mg testosterone)}. others, and avoid shower or bath for 6 h. Avoid skin contact with others at application site (especially pregnant women and children). Oral Testosterone for example, Restandol 40 mg Usually 1 or 2 three times daily
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328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346
350 351
290
298
327
349
287
295
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348
285
294
325
347
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289
322 324
283
288
321 323
Options for prescription
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recommend if clinically indicated on the basis of symptoms or PSA in those >40 years old.
Mucoadhesive buccal tablets for example, Striant SR 30 mg Testosterone implant 100 mg–600 mg Testosterone patches (eg, Andropatch 5 mg/ 24 h)-currently withdrawn by manufacturer
Twice daily Variable, up to 4–5 months. Patch applied to clean, unbroken skin of back, abdomen, upper arms or thighs-usually starting at 5 mg at 2200hrs and replacing after 24 h on a different site (interval of seven days before re-using same site).
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352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367
Testosterone concentrations should be measured in the mornings, 2 hours after the gel has been applied. Can assess testosterone 2 weeks after started. Tostran maximum dose is 80 mg testosterone.
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Variable serum levels-due to variable bioavailability following first-pass metabolism. No ideal time to monitor levels. Assess testosterone levels immediately before application of fresh system. Assess pre-dose testosterone Dose range: 2.5 mg/24 h to 7.5 mg/24 h (latter may especially be needed in those >130 kg). Local irritation can be problematic. Monitor testosterone 3–12 h after application, usually on morning sample (as early as after 3 days).
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Abstracts 385
Table 3 Testosterone replacement therapy-abbreviated case reports from the Defence Medical Rehabilitation Centre (DMRC), Headley Court
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Mechanism of injury
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Injuries sustained
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Testosterone on arrival at DMRC Treatment Testosterone post-treatment
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IED-2010
IED-2010
Bilateral above knee amputations, left orchidectomy, multiple soft tissue wounds, persistent sweating a significant problem 5.1
Left hip disarticulation, right femoral fracture, loss of one testicle at scene, second non-viable at surgery 1.0
Bilateral above knee amputations, right orchidectomy, left testicular damage-successful sperm salvage at time of injury 0.7 and 0.9
Nebido 19 (with relief of sweating)
Nebido 18 (April 2011)
Nebido 8.5 (after 3 months, with relief of low mood, fatigue, sweating)
400 401 402 403
406 407 408 409 410 411 412 413 414 415 416 417 418 419
453 454 455 456 458 459 460 461 462
following blast injury we feel it is important to achieve therapeutic testosterone levels rapidly not only for the sake of the individual’s symptom relief (sweating, low mood, reduced libido etc) but also to maximise their rehabilitation potential.
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452
457
398 399
450 451
IED-2009
IED, Improvised Explosive Device.
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449
Monitoring Monitoring of TRT is normally undertaken three months after commencement of treatment and annually thereafter. However, earlier and more frequent assessment can be justified in this population, especially when undergoing inpatient rehabilitation and testosterone levels may be assessed as guided by the advice in Table 2. The aim of monitoring is three-fold: to establish that testosterone levels are reasonably within therapeutic target (generally in the middle of the normal reference range); that there has been a clinically beneficial response to treatment (this may be in terms of erectile function, bone density, absence of sweating, feeling of well being etc) and to detect any adverse effects such as acne or mood swings. An outline of a suggested monitoring programme is suggested in Table 4. Table 2 gives details about
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when to monitor testosterone dependant on the preparation used, generally the aim is to achieve testosterone levels in the mid-reference range but symptom assessment is an important part of monitoring and may necessitate achieving testosterone levels at the upper end of the reference range. Similarly, if a patient has good erectile function, needs to shave every day and feels well there is no need to be overly concerned by a testosterone in the lower half of the reference range. It is important to appreciate that although TRT stimulates prostatic growth and exacerbates pre-existing prostatic cancer7 8 there is no good evidence that TRT increases the risk of prostate cancer per se.9 The PSA may often rise from the low-normal range to high-normal, as a result of prostatic growth. A recent meta-analysis10 of TRT found no significant effect on mortality, prostate, or cardiovascular outcomes. The latter point is particularly relevant since TRT may cause a very slight fall in HDL but the clinical significance of this is uncertain.10 Finally, it may be helpful to ask patients on buccal testosterone about any changes in taste and to examine gums for irritation and to examine the skin for irritation in those on patches. Competing interests None.
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Table 4 Monitoring of testosterone replacement therapy
422 423
Investigation
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Interval
Comment
Provenance and peer review Not commissioned; internally peer reviewed.
REFERENCES 1
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Testosterone
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Baseline, 3 months and then annually if stable.
427 428
Bone mineral density
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Pre-treatment and if osteoporotic or low trauma fracture repeat at 3 years.
432
PSA/Prostate/ review of prostatic symptoms
433 434 435
Baseline, 3 months and then annually if stable
436 437 438 439 440 441
Haematocrit (Hct)
442 443
Baseline, 3 months and then annually
444 445
Calcium
446 447
Baseline, and annually
PSA, Prostate Specific Antigen.
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4
Aim for mid normal local reference range. Can be assessed sooner if clinically justified. Uncertain if strictly necessary in young military population with genital trauma, but monitoring every 5 years would seem reasonable Seek urology opinion if rising or elevated PSA. European guidelines recommend a rectal examination of the prostate in addition to PSA at baseline, 3 months and then ‘according to evidence-based guidelines’ thereafter. Not usually done by UK Endocrinologists in men under 40 years. If >0.54 STOP therapy, evaluate patient for other causes. When/if Hct falls may restart therapy at lower dose. Testosterone may very rarely elevate calcium.
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4
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6
7
8
9
10
Spratt DI, O’Dea LS, Schoenfeld D, et al. Neuroendocrine-gonadal axis in men: frequent sampling of LH, FSH, and testosterone. Am J Physiol 1988;254:E658–66. Sewani-Rusike CR, Mudambo KS, Tendaupenyu G, et al. Effects of the Zimbabwe Defence Forces training programme on body composition and reproductive hormones in male army recruits. Cent Afr J Med 2000;46:27–31. Rosner W, Auchus RJ, Azziz R, et al. Utility, limitations and pitfalls in measuring testosterone: an Endocrine Society Position Statement. J Clin Endocrinol Metab 2007;92:405–13. Brambilla DJ, O’Donnell AB, Matsumoto AM, et al. Intraindividual variation in levels of serum testosterone and other reproductive and adrenal hormones in men. Clin Endocrinol 2007;67:853–62. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 1999;84:3666–72. Nieschlag E, Vorona E, Wenk M, et al. Hormonal male contraception in men with normal and subnormal semen parameters. Int J Androl 2011. doi:10.1111/j. 1365-2605.2011.01142.x Bhasin S, Cunningham GR, Hayes FJ, et al. Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:2536–59. Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations. Eur J Endocrinol 2008;159:507–14. Roddam AW, Allen NE, Appleby P, et al. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst 2008;100:170–83. Fernández-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2010;95:2560–75.
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