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Keywords:

  • erectile dysfunction;
  • hypogonadism;
  • Nebido;
  • nitric oxide;
  • testosterone undecanoate

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. Author contributions
  10. References

Hypogonadism, which is highly prevalent in men with sickle cell disease (SCD), affects quality of life and causes great morbidity. The safety of testosterone replacement therapy (TRT) in SCD in relation to priapism episodes is relatively unknown. Our aim was to monitor the safety of TRT in a cohort of seven hypogonadal men with SCD. Testosterone undecanoate (Nebido) 1 g was administered intramuscularly to adult men with homozygous SCD (Hb SS) having hypogonadism [serum total testosterone ≤12.0 nmol/L (346 ng/dL), reference range 12.5–38.1 nmol/L (360–1098 ng/dL)] for 12 months. Serum total testosterone, haemoglobin, haematocrit, renal and liver function tests, glucose and PSA measurements were done at baseline and 12-month follow-up. Trough serum total testosterone, haemoglobin and haematocrit were measured three monthly. Priapism events and adverse drug events were assessed every 3 months. International Index of Erectile Function (IIEF), Androgen Deficiency in the Ageing Male (ADAM) and World Health Organization Quality of Life (WHOQOL) questionnaires were administered at baseline, 6 and 12 months. Seven men with a mean age of 34.4 years were treated. Median total testosterone increased from 10.6 to 11.2 nmol/L (p = 0.46). Median serum lactate dehydrogenase levels decreased from 1445 to 1143.5 IU/L (p < 0.05), while all other laboratory indices remained stable. Injection site pain was the most frequently reported adverse event, with no increases in painful crises, hypersensitivity or oedema. After TRT, there was no significant increase in priapism frequency. Median questionnaire scores were increased for the IIEF (46–68, p = 0.018), reduced for ADAM (5.0–2.0, p = 0.016) and unchanged for WHOQOL (98–103, p = 0.086). TRT using testosterone undecanoate with eugonadal intent for hypogonadism appears to be safe in men with SCD. This treatment does not appear to promote priapism occurrences and rather it possibly improves sexual function. Future prospective evaluations in larger groups of hypogonadal men with SCD are necessary to confirm these findings.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. Author contributions
  10. References

Hypogonadism is a clinical syndrome that results from failure of the testes to produce physiological levels of testosterone because of disruptions of one or more levels of the hypothalamic–pituitary–testicular axis (Bhasin et al., 2010). Longitudinal studies show an annual decline of 1–2% in total testosterone levels after 40 years of age (Feldman et al., 2002). In middle aged and older men, the prevalence of symptomatic hypogonadism is between 6 and 12% (Araujo et al., 2004). Signs and symptoms of hypogonadism include sexual disturbances (reduced libido, erectile dysfunction), infertility, metabolic abnormalities (glucose intolerance, hypercholesterolaemia, increased abdominal adiposity, osteoporosis) and cognitive and mental disturbances (depression, memory loss, difficulty concentrating, easy fatigability and anxiety). Hypogonadism has now been linked to insulin resistance, obesity and the metabolic syndrome (Corona et al., 2011). There is increased cardiovascular morbidity and mortality in patients with hypogonadism (Corona et al., 2011). In young boys, hypogonadism affects normal growth and development and metabolism (Singhal et al., 1995).

Sickle cell disease (SCD) is a common genetic disorder because of inheritance of the gene for haemoglobin S (Serjeant & Serjeant, 2001). The sickle haemoglobin is caused by a point mutation resulting in the substitution of valine for glutamic acid in the sixth position of the β-globin gene on chromosome 11. Hypogonadism has been demonstrated in adolescents and young adult males with SCD (Olambiwonnu et al., 1975; Abbasi et al., 1976; Osegbe & Akinyanju, 1987; Parshad et al., 1994). The aetiology is thought to be either a primary testicular pathology (Abbasi et al., 1976; Osegbe & Akinyanju, 1987; Parshad et al., 1994) or hypothalamo–pituitary dysfunction (Dada & Nduka, 1980).

Testosterone replacement therapy (TRT) is usually recommended in men with hypogonadism who are symptomatic (Bhasin et al., 2010). Treatment aims to alleviate symptoms and restore hormone levels to normal. In children with growth delays, exogenous testosterone promotes growth and pubertal development. TRT has been associated with adverse events such as erythrocytosis, acne and oily skin, reduced sperm production and fertility, gynecomastia, male pattern balding and growth of breast cancer (Bhasin et al., 2010). TRT may worsen obstructive sleep apnoea, severe lower urinary tract symptoms and congestive cardiac failure (Bhasin et al., 2010). The intramuscular formulations may be associated with injection site pain and cough (Mackey et al., 1995). Though there are fears that TRT may increase the growth of metastatic prostate cancer (Fowler & Whitmore, 1982), there is no evidence to suggest that TRT will cause prostate cancer de novo (Feneley & Carruthers, 2012).

Priapism, defined as a persistent penile erection that continues beyond, or is unrelated to, sexual stimulation (Montague et al., 2003), is perceived to be a risk of TRT in hypogonadal males although systematic evaluation of this possibility is lacking. Case reports suggesting this association, however, have mostly been associated with administration of testosterone analogues, e.g. testosterone enanthate which result in supra-physiological plasma levels of testosterone (Zelissen & Stricker, 1988; Key et al., 1989; Zargooshi, 2000). Widespread TRT is certainly not practised in men with SCD, who are known to have high rates of ischaemic priapism (Mantadakis et al., 1999). The question of the safety of TRT in men with SCD is even more pronounced, for fear of inducing priapism episodes in an already high-risk population of males (Slayton et al., 1995). The association of priapism in hypogonadal males with SCD undergoing TRT has only been reported in the literature twice (Lundh & Gardner, 1970; Slayton et al., 1995). However, a definitive causal association has never been proven.

The adverse effects of hypogonadism in adolescent and adult males not only impair quality of life, but they also increase morbidity. If testosterone can be safely given to patients with SCD, they can be treated for many of the adverse effects of hypogonadism. Our aim was to monitor the safety of TRT in a small cohort of hypogonadal men with SCD. Accordingly, this study may serve as a Phase 1 uncontrolled open-label trial assessing the safety of TRT in hypogonadal men with SCD.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. Author contributions
  10. References

Study design

Men with homozygous SCD (Hb SS) attending the Sickle Cell Unit, University of the West Indies, Jamaica for health maintenance visits were evaluated for symptomatic hypogonadism and enrolled in this open-label, uncontrolled study from December 2010 to March 2012. Symptomatic hypogonadism was defined as low total testosterone levels in combination with signs and symptoms of androgen deficiency. The Sickle Cell Unit of the University of the West Indies, located in Kingston, Jamaica is the only specialized centre providing comprehensive care for persons with SCD in the English-speaking Caribbean. The centre is a non-referral unit and any patient with any of the SCDs who wishes to attend is registered and provided with clinical care.

Testosterone undecanoate (Nebido; Bayer Health-care, Berlin, Germany) 1 g was administered intramuscularly by protocol as an initial dose, with a repeat dose at 6 weeks and then repeated dosing every 3 months thereafter for 12 months (Yassin & Saad, 2006).

Key inclusion and exclusion criteria

Hypogonadism was defined as a total testosterone ≤12.0 nmol/L (346 ng/dL) with reference lab range of 12.5–38.1 nmol/L (360–1098 ng/dL). Although there is no generally accepted cut-off value of plasma total testosterone for defining androgen deficiency, a recent study reported a cut-off value of 12.1 nmol/L (348.3 ng/dL) in a community-based sample of young men (Bhasin et al., 2011). Exclusion criteria included acute illnesses, endocrine disorders apart from hypogonadism, history of prostate or breast cancer, history of sleep apnoea, current use of testosterone therapy or hypersensitivity to testosterone undecanoate (Nebido).

Clinical assessments

Baseline clinical examination included measurement of weight (kg) using a beam balance and height (m) using a staidometer. A genitourinary examination was conducted and testicular size was measured, male hair distribution and presence or absence of gynecomastia was noted, and a prostate exam was performed. Breast and cardiovascular exams were also performed to exclude breast masses, gynecomastia or cardiac abnormalities.

Serological testing including prostate specific antigen (PSA), total testosterone, haemoglobin, haematocrit, cholesterol, renal and liver function tests and glucose was carried out between 8 and 10 am at baseline. Sera were separated immediately and stored at −20 °C until assayed. Total testosterone was measured with the IMMULITE 2000 Analyzer chemiluminescent enzyme immunoassay. Total testosterone was measured on two occasions in the morning prior to study enrolment (Bhasin et al., 2010). Quantitative estimation of lactate dehydrogenase (LDH) was performed with VITROS Chemistry Kit (Ortho-Clinical Diagnostics Inc., Rochester, NY, USA). LDH catalyses the reversible reduction of pyruvate to lactate using nicotinamide adenine dinucleotide (NADH). The oxidation of NADH, which is monitored by reflectance spectrophotometry, is used to measure LDH activity.

At baseline, all study participants completed the International Index of Erectile Function (IIEF) (Rosen et al., 1997), the Androgen Deficiency in the Ageing Male (ADAM) (Morley et al., 2000) and the World Health Organization Quality of Life (WHOQOL)-BREF (World Health Organization Quality of Life Group, 1998) questionnaires. Study participants also completed a non-validated priapism questionnaire indicating history of episodes and frequency. The IIEF is a validated 15-question instrument used to assess overall sexual satisfaction in five domains: erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction. The ADAM questionnaire is a 10-item screening tool used for identifying androgen deficiency in ageing men. If a participant responds affirmatively to decreased libido or strength of erection or gives a positive response to any three of the non-specific questions including fatigability, decreased muscle strength, mood change and loss of height, he is considered as having symptoms suggestive of androgen deficiency.

The WHOQOL-BREF is a validated instrument used to measure quality of life with four domains: physical, psychological, social and environment health. There are no norms for the WHOQOL-BREF in the Jamaican sickle cell population; however, the instrument appears to have good psychometric properties for use in assessing quality of life in patients with SCD (Asnani et al., 2009).

Main outcome measures

All study participants had serum total testosterone, haemoglobin and haematocrit measured at each 3-month visit and repeat complete serological testing at the 12-month follow-up visit. Blood was taken immediately prior to the next testosterone injection. In addition, priapism events and adverse events including painful crises, leg and breast swelling, and drug sensitivity were assessed at each 3-month visit. All questionnaires were repeated at 6- and 12-month follow-up visits.

Statistical analysis

Summary values are expressed as means with standard deviation or medians with interquartile ranges. Differences between pre-treatment and post-treatment median values were assessed using the Wilcoxon signed-rank test. A p value <0.05 was considered significant. Data were analysed using Stata 12 for Windows (College Station, TX, USA).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. Author contributions
  10. References

Patient characteristics and testosterone measurements

Seven men with a mean age of 34.4 ± 6.8 years and median serum total testosterone level of 10.6 nmol/L were treated (Table 1). Mean height and weight were 178.7 ± 4.8 cm and 66.0 ± 10.2 kg respectively. Post-treatment serum total testosterone levels of the five patients who completed 12 months of treatment (cases 2, 4–7) increased to a median value of 11.2 nmol/L (p = 0.46) (Table 2).

Table 1. Summary of biochemical parameters: pre-treatment with Nebido
VariablePatient 1Patient 2Patient 3Patient 4Patient 5Patient 6Patient 7All patients
  1. ALT, alanine transaminase; AlkPO4, alkaline phosphatase; Bili, bilirubin; LDH, lactate dehydrogenase; PSA, prostate specific antigen.

  2. Values are medians with interquartile ranges.

Haemoglobin (g/dL) [14–18]11.78.49.65.35.47.96.97.9, 4.2
Haematocrit (%) [0.42–0.52]0.340.250.310.150.160.250.20.3, 0.2
Glucose (mmol/L) [<10]54.35.65.54.55.64.85, 1.1
Creatinine (μmol/L) [0–140]7168597165425265, 19
ALT (IU/L) [7–41]223766192026 22, 17
ALK PO4 (IU/L) [38–126]119113832818313789113, 54
Total Bili (μmol/L) [3.4–25.6]107.350.143.735.52433114.543.7, 74.3
Direct Bili (μmol/L) [0–6.8]04.65.810.44.73.35.94.7, 2.6
LDH (IU/L) [313–618]1521133814561483144583212181445, 265
Testosterone (nmol/L) [12.5–38.1]10.210.87.510.710.610.211.710.6, 0.6
PSA (ng/mL) [0–4]0.780.760.570.260.290.610.210.6, 0.5
Table 2. Summary of biochemical parameters: post-treatment with Nebido
VariablePatient 1Patient 2Patient 3Patient 4Patient 5Patient 6Patient 7All patients
  1. Patient 1 abandoned treatment after 9 months because of a desire for fertility. Recorded post-treatment testosterone value is that at 12 months; where last dose of Nebido was given at 6 months.

  2. Patient 3 demised at 9 months.

  3. ALT, alanine transaminase; AlkPO4, alkaline phosphatase; Bili, bilirubin; LDH, lactate dehydrogenase; PSA, prostate specific antigen.

  4. Values are medians with interquartile ranges.

  5. a

    p < 0.05 comparing pre- and post-treatment values.

Haemoglobin (g/dL) [14–18]11.88.45.65.46.96.96.9, 2.8
Haematocrit (%) [0.42–0.52]0.350.250.160.160.220.20.21, 0.09
Glucose (mmol/L) [<10]6.74.564.65.15.95.5, 1.4
Creatinine (μmol/L) [0–140]67657470455266, 18
ALT (IU/L) [7–41]2030361929 29, 10
ALK PO4 (IU/L) [38–126]99943127615499, 60
Total Bili (μmol/L) [3.4–25.6]15438.842.5241886.740.65, 62.7
Direct Bili (μmol/L) [0–6.8]01.15.11.12.201.1, 2.2a
LDH (IU/L) [313–618]12781229995119062510971143.5, 234a
Testosterone (nmol/L) [12.5–38.1]7.422.88.710.811.217.611.2, 8.9
PSA (ng/mL) [0–4]0.50.570.240.830.610.190.53, 0.37

Laboratory determinations

Haemoglobin and haematocrit were below normal ranges at baseline, as expected for this patient population, and did not change after 12 months of therapy (Tables 1 and 2). Similarly, renal and liver function tests and glucose serological tests were unchanged from baseline levels after 12 months of therapy (Tables 1 and 2). Mean serum total bilirubin and alkaline phosphatase measurements were above normal ranges at baseline (Table 1), with no further changes after 12 months of therapy (Table 2). Median serum LDH levels were above normal ranges at baseline and decreased after 12 months of therapy (Tables 1 and 2). Median serum PSA was assessed to be in the low normal range (0.6 ng/mL) at baseline, with no significant change after 12 months of therapy (p = 0.39) (Tables 1 and 2).

Questionnaire scores

Median IIEF questionnaire scores increased from IIEF 46 at baseline to 68 at 12 months, (p < 0.05), with significant improvements in the domains of desire (p < 0.05), intercourse satisfaction (p < 0.05), overall satisfaction (p < 0.05) (Fig. 1, Table 3).

Table 3. Comparison of baseline and follow-up IIEF domains
SubjectsPre-erectile functionPost-erectile functionPre-orgasmic functionPost-orgasmic functionPre-desirePost- desirePre-intercourse satisfactionPost-intercourse satisfactionBaseline overall satisfactionPost-overall satisfaction
  1. IQR, interquartile range; IIEF, International Index of Erectile Function.

  2. a

    p < 0.05 comparing pre-treatment median to post-treatment median.

13030101076121488
2130074100958
3173081161091069
429291010891012610
55400670048
6327010790988
721301010810814410
Median, IQR17, 2630, 38, 1010, 37, 29, 3a8, 1010, 5a6, 48, 2a
image

Figure 1. Comparison of Questionnaire scores. Values are median with minimum and maximum. IIEF, International Index of Erectile Function Questionnaire; ADAM, Androgen Deficiency in the Ageing Male Questionnaire; WHOQOL-BREF, World Health Organization Quality of Life-BREF Questionnaire.

Download figure to PowerPoint

All study participants satisfied criteria as having symptoms of androgen deficiency at baseline using the ADAM questionnaire. Mean ADAM symptom scores reduced by 60% after 12 months of TRT (Fig. 1). All study participants negatively responded to questions regarding reduced libido and reduced erections after 12 months of TRT.

There was no significant change in the scores for the WHOQOL-BREF from baseline to 12-month follow-up (p = 0.86) (Fig. 1). Total raw and transformed scores on the WHOQOL-BREF before and after TRT were lower than reported population norms.

Questionnaire data were similar for 6 month (data not shown) and 12-month follow-up clinic visits.

Priapism histories

Four men reported prior episodes of priapism with two men having frequency of episodes of 2–5 and >20 times per year respectively (Table 4). The other two reported no priapism episodes within the 12 months prior to enrolment, with lifetime episodes of 5 and >20 episodes. During TRT, there was no evidence of increased priapism episode frequency in men who had prior episodes of priapism. One study participant (case 5) reported an episode of priapism during TRT lasting for 4 h which resolved spontaneously at home. Three men gave no prior history of priapism. Case 6 had a nocturnal episode of priapism which awakened him from sleep and lasted for a further 30 min before resolving spontaneously. There was no significant increase in priapism episodes after TRT.

Table 4. Priapism frequency (per 12 months) in study patients before and after 12 months of testosterone treatment
 Priapism historyBaseline frequencyFollow-up frequency
Case 1Positive2–51
Case 2Positive0–10
Case 3Negative00
Case 4Positive0–10
Case 5Positive>20>10
Case 6Negative01
Case 7Negative00

Adverse events and discontinuations

Injection site pain was the most frequently reported adverse event. There was no increase in the number of painful crises, hypersensitivity or pedal oedema. There was no evidence of breast or leg swelling. There were no adverse cardiovascular events.

Case 3 demised after 9 months of follow-up because of acute chest syndrome. Case 1 abandoned treatment after 9 months because of a desire for fertility and confirmed azoospermia on semen analyses.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. Author contributions
  10. References

Our study revealed that TRT is safe in hypogonadal men with SCD and does not increase episodes of priapism. Our study also suggests that TRT offers therapeutic benefit for these men, based on improvements in monitored sexual dysfunction symptoms.

These findings are quite important as hypogonadism is common in SCD but often goes untreated because of perceived safety fears associated with TRT. The burden of hypogonadism affects quality of life and may impair morbidity and increase mortality (Saad & Gooren, 2011). This impact may be even greater in the SCD population (Olambiwonnu et al., 1975; Singhal et al., 1995).

We consider these results meaningful despite the lack of a statistically significant increase in testosterone levels aggregately for our study group. Though desired mid-range serum testosterone levels were not achieved in all men, acceptable levels were attained in cases 2 and 7 in whom there was no increase in priapism episodes. Variability in testosterone level increases with TRT may be a peculiarity of men with SCD, in view of lacking reference intervals in this unique population. SCD is a metabolic disorder that features varied haematological and clinical presentations, which may affect individual testosterone levels. Importantly, the impact of the exogenous testosterone exposure using our treatment formulation and schedule is suggested based on its apparent amelioration of hypogonadal symptoms.

Intercourse satisfaction and sexual desire domains of the IIEF questionnaire were improved in our group overall after 12 months of treatment. The efficacy of testosterone undecanoate is in keeping with other reports of this therapy in other populations (Moon du et al., 2010; Zitzmann et al., 2012).

Our study also showed an improvement in serum LDH levels after TRT. Serum LDH has been used as a biomarker of SCD activity and haemolysis-associated endothelial dysfunction and end organ vasculopathy (Kato et al., 2006). Though the increase in testosterone levels was modest, TRT possibly yielded an improvement in disease severity of SCD.

The fear of providing TRT in men with SCD was because of the perceived role of testosterone in precipitating priapism episodes (Slayton et al., 1995). Androgens are certainly important in regulating erectile function (Saad et al., 2007) and promoting penile growth and development (Traish & Kim, 2005). Circulating androgens maintain structure and function of pelvic ganglion nerves supplying the penis (Meusburger & Keast, 2001) as well as trabecular smooth muscle comprising the penis (Bivalacqua et al., 2012). Androgens also play an important regulatory role in the functions of molecular factors involved in penile erection. They regulate the expression of nitric oxide synthase (NOS), and castrated animals have reduced NOS expression levels which are restored after testosterone treatment (Zvara et al., 1995). Androgens are critical for maintaining normal expressions of phosphodiesterase (PDE) type 5 (PDE5) in the penis. Androgen deprivation reduces PDE5 expression in animal models while testosterone supplementation restores PDE5 gene and protein expressions (Morelli et al., 2004).

Recently, much has been learned about the molecular mechanisms underlying priapism. This research emphasizes the integral role of nitric oxide (NO) in the molecular science of priapism. The classic paradigm of venous occlusion in the penis as a cause for priapism has been challenged by the newer theory of dysregulation involving NO signalling, leading to priapism (Burnett, 2006). NO is important for penile erection as well as maintaining vascular homeostasis (Burnett et al., 2006). PDE5 terminates NO-induced cGMP-mediated cavernosal smooth muscle relaxation. Haematological disorders such as SCD that disturb normal vascular homeostasis induce abnormal NOS activity/reduced NO bioavailability in the penis (Morrison & Burnett, 2012). Dysregulation of the NO system ultimately affects smooth muscle tone, which controls penile tumescence and detumescence. Transgenic sickle cell mice have reductions in penile NO/cGMP signalling leading to deficient PDE5 function and uncontrolled erectile responses (Champion et al., 2005). The RhoA/Rho-kinase vasoconstrictive pathway that opposes the NO signal transduction pathway is also downregulated when NO signalling function is impaired (Bivalacqua et al., 2007). Because the cavernosal smooth muscle control system is dysfunctional in priapism, responses to normal erectile stimuli (sexual or sleep related) are uncontrolled (Burnett & Bivalacqua, 2007).

The specific cause of hypogonadism in SCD remains unknown. Several studies have documented a primary testicular pathology, which could be secondary to vaso-occlusion of testicular vessels (Parshad et al., 1994). Other possible mechanisms have been postulated, including abnormal binding of pituitary hormones to testicular receptors and abnormality of testicular steroidogenesis (Abbasi et al., 1976). However, several studies have also reported secondary hypogonadism, secondary to possible pituitary infarction (Dada & Nduka, 1980). In addition, Prasad et al. (1975) theorized that androgen deficiency in patients with SCD may be related to zinc deficiency.

It seems incongruous that in the same population of men who are at increased risk of priapism, a high prevalence of hypogonadism is observed. If we believe the notion that high circulating levels of testosterone trigger priapism episodes, then priapism tendencies would be inconsistent in men with SCD who are often testosterone deficient. Given that androgens are important in modulating functions of NOS and PDE5 enzymes, we have hypothesized that in hypogonadism such molecular modulation may be affected (Pierorazio et al., 2011). We further hypothesize that molecular abnormalities involving NO/cGMP signalling in the penis may be exacerbated in SCD patients with hypogonadism, contributing towards their priapism phenotype. As such, we theorize that TRT will not worsen but rather alleviate episodes of stuttering priapism in patients with SCD. Recent study has shown that testosterone administration to transgenic SCD mice, which have low systemic testosterone levels, partly corrects their priapism phenotype (Burnett AL, Lagoda G, Sezen SF, Musicki B, unpublished observations).

Priapism as a result of TRT is a rare complication. Most case reports suggesting this association have involved testosterone preparations that resulted in supra-physiological levels of testosterone in the serum (Key et al., 1989). None have firmly established exogenously administered testosterone to be a cause of priapism. The literature only describes two reports of this complication in patients with SCD, both associated with injectable testosterone administration that possibly produced supra-physiological dosing effects (Lundh & Gardner, 1970; Slayton et al., 1995). In contrast, a recent systematic review of transdermal AndroGel 1% use in three randomized, controlled clinical trials of hypogonadal men (none of whom had SCD) did not demonstrate any cases of priapism associated with this TRT formulation (Burnett et al., 2013). Similarly, testosterone undecanoate, which was used in our study, does not result in supra-physiological levels of plasma testosterone and hence may be considered a relatively safe formulation for TRT.

We acknowledge several limitations of our study. The study sample consisted of a small, heterogenous group of men with varying frequency and severity of prior priapism episodes. The increase in serum testosterone levels seen after 12 months was modest, which may differ from the effects of TRT that produces mid-normal range serum testosterone levels. Measurement of serum trough levels in our patients after 12 weeks may have impacted on the modest post-treatment testosterone levels. Previous experience with testosterone undecanoate shows trough levels at 10 weeks of 10.4 nmol/L (Wang et al., 2010). Perhaps post-treatment measurements at 4–6 weeks would have yielded higher values. The mean age of our sample was quite young, and the normal total and free testosterone references ranges for healthy young men vary widely. Therefore, the target serum testosterone level that may be sought for young hypogonadal patients with SCD remains unclear and requires further study. Although there were no demonstrable haematological, cardiopulmonary or genitourinary consequences of TRT in these patients, rigorous monitoring of pulmonary and cardiovascular status, e.g. echocardiography, sleep laboratory tests, was not performed in this study. Such evaluations can be included in subsequent clinical research studies evaluating the safety of TRT in men with SCD.

Our pilot study comprised young hypogonadal men with SCD, in their reproductive years that could potentially have future paternity desires. TRT is associated with azoospermia, which may be reversible (Jan et al., 2012). SCD is also independently associated with semen abnormalities and infertility (Osegbe & Akinyanju, 1981). Sickle cell patients with symptomatic hypogonadism should be strongly counselled about the risk of infertility prior to treatment. Semen analyses before TRT may be considered in this patient population.

In summary, we report results from a small pilot investigation with an extended interval of clinical monitoring showing the safety and possible utility of TRT in hypogonadal men with SCD. This experience exceeds prior literature reports on this topic and conceivably presents a paradigm shift by opposing conventional notions regarding TRT in the SCD population. This therapy actually may address multiple aspects of the hypogonadal condition in men with SCD, and further studies evaluating TRT in men with SCD may demonstrate various possible health benefits beyond its apparent positive effect on sexual function that was a primary focus of this report. Given the possibility that androgen deficiency exacerbates mechanisms involved in the molecular biology of ischaemic priapism, we speculate that TRT actually may be useful in prophylaxis of stuttering priapism in the SCD patient population by way of normalizing erectile mechanisms. We acknowledge that this report does not constitute an efficacy study and forthcoming studies involving TRT rigorously designed for this additional purpose are required to support recommendations for its use in treating priapism. However, our report here provides preliminary support for exogenously administered testosterone with eugonadal intent in men with SCD as offering potential clinical benefit for hypogonadism without constituting major safety risks including induction of priapism.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. Author contributions
  10. References

This study was supported by the New Initiative Grant, University of the West Indies, Jamaica.

Author contributions

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. Author contributions
  10. References

BM performed the research, analysed the data and drafted the manuscript. MR contributed to data acquisition, contributed to research design, contributed essential reagents and tools. WM performed the research, contributed essential reagents and tools. AB drafted the manuscript and involved in critical revision, approval of submitted and final version.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflicts of interest
  9. Author contributions
  10. References