Long-term testosterone treatment with different testosterone preparations

- provocative results on diagnosis and adherence

Long-term testosterone treatment with different testosterone preparations

Due to lack of consistent clear-cut guidelines for diagnosis and treatment of testosterone deficiency, there is a lot of confusion among both health professionals and suffering men. The multiple different testosterone preparations available further add to the complexity of testosterone treatment.

This editorial presents the intriguing results from a notable study that analyzed effects of testosterone therapy with seven different testosterone preparations, in symptomatic men who had previously been denied treatment because of "normal" baseline testosterone levels.1 The results are quite provocative and highlight several important practical issues relating to diagnosis and treatment of hypogonadism…

KEY POINTS

  • Symptoms indicative of testosterone deficiency do not correlate with either total or free testosterone levels a baseline. Symptomatic patients with testosterone levels in the “normal range” benefit as much as do those with very low testosterone levels.
  • Symptomatic relief may require longer than 1 year to achieve – this underscores the critical importance of long-term adherence to testosterone therapy. This contrasts with the common clinical practice of only giving testosterone therapy to men for 3-6 months to “see if it works".
  • Treatment with testosterone undecanoate injections may confer better symptomatic resolution than other preparations during the first year of treatment.
  • None of the commonly available testosterone preparations cause any adverse effects on prostate or cardiovascular related parameters.
  • While all commonly available testosterone preparations are safe and effective, risk of excessive increases in hemoglobin or hematocrit and polycythemia may be greater with pellet implants or transdermal testosterone.

What is known

Diagnosis and treatment of testosterone deficiency is a complex issue, for many reasons. Symptoms that may be indicative of testosterone deficiency are not specific to this condition, and may be related to co-morbidities.2,3 Despite proposed testosterone thresholds by clinical guidelines (which are not universally agreed upon) there is no single testosterone level – which applies to all men - at which symptoms and signs indicative of testosterone deficiency start to develop.4,5

Further complicating the issue of diagnostic testosterone thresholds is the tremendous variability in testosterone assays – each giving different readings - and assay specific reference ranges that vary between labs.6,7 In addition, because of differences in androgen receptor sensitivity, among men with the same testosterone level, some may suffer hypogonadal symptoms, while others don’t.8

Adding to this complexity are the multiple available testosterone treatment options.9,10 Available testosterone preparations include transdermal, intramuscular injections, oral, sublingual/buccal and pellet implants. Each has its own pros and cons that need to be considered when treating hypogonadal men.

What this study adds

The study by Carruthers et al. reports clinical experience with seven different testosterone preparations available in the UK.11 The goal was to investigate symptom response to testosterone treatment with testosterone undecanoate injections, pellet implants, scrotally applied gel, scrotally applied cream, transdermal testosterone gel, oral testosterone undecanoate or mesterolone. In addition, effects on endocrine, biochemical and physiological responses to the different preparations were investigated.

The study

2247 men, mean age 54 years (range 20-90 years) attending the 3 Men’s Health Centers were treated with one of seven different testosterone preparations.

A notable aspect of this study is that diagnosis was made on the basis of clinical signs and symptoms alone – regardless of baseline testosterone levels - and it included many patients who had previously been declined treatment by their doctors because they were deemed to have testosterone levels in the "normal" range. Overall, only 31% of men had pre-treatment total testosterone levels below 12 nmol/L (346 ng/dL), a commonly used threshold required for the diagnosis of hypogonadism, as proposed by several clinical guidelines.12,13

Correlation of baseline testosterone levels with symptom severity and symptom resolution

Surprisingly to many, it was found that baseline total testosterone and free testosterone (calculated) levels were totally unrelated to the initial symptom score (which was the reason for patients attending the clinic for treatment). Also, there was no association between initial symptom score and baseline estradiol or SHBG. This is consistent with results from other studies showing failure of hormone parameters to correlate with testosterone deficiency symptoms.14,15 This clearly shows that sole reliance on testosterone levels is inappropriate when evaluating men for testosterone deficiency.

Comparing the symptomatic responses to treatment in the patients with initial total testosterone levels below 12 nmol/l (mean 9.6 nmol/l) with those greater than or equal to 12 nmol/l (mean 19.1 nmol/l), there was no significant difference between either the initial symptom scores or their response to treatment for up to 12 years, regardless of testosterone preparation used for treatment. This can be explained by inter-individual differences in androgen receptor sensitivity, which makes some men resistant to the effects of testosterone.8 Those men can have markedly higher testosterone levels but still experience the same degree of symptoms as do men with much lower levels.

Symptom resolution as a function of testosterone preparation and treatment duration

Comparing the different testosterone preparations if was found that testosterone undecanoate injections performed very well in terms of symptom resolution. However, among patients who did not achieve resolution of symptoms during the first year of testosterone treatment, those who stayed on treatment eventually did achieve significant symptomatic benefit compared to baseline.

Thus, even subjective symptoms (not only biochemical parameters and cardiometabolic risk factors) may take longer than 1 year to resolve. This is an important finding as many doctors discontinue testosterone treatment in patients who do not experience symptomatic improvement within 3 to 6 months after start of testosterone therapy. It also suggests that the previously suggested duration for a testosterone treatment trial of 3 months in symptomatic men16 may not be enough to allow for symptomatic relief.

Safety of the different testosterone preparations

The safety factors monitored using these preparations, including renal and liver function tests, remained normal. Also, there was no clinical evidence of either increased cardiovascular events or venous thrombosis. Cardiovascular risk factors either did not change or improved (reduction in cholesterol and diastolic blood pressure).

Key findings and conclusion

This study highlights two important issues relating to diagnosis and treatment of testosterone deficiency:

  1. Symptoms of testosterone deficiency do not correlate with testosterone levels. This contradicts clinical practice guidelines which require a combination of symptoms and “unequivocally low testosterone levels” to make the diagnosis of testosterone deficiency3,12,13, but supports the view of other researchers that initiation of testosterone treatment should rely more on symptoms and less on a discrete numerical testosterone level thresholds.17

  2. Symptomatic relief may require longer than 1 year to achieve. This may contribute to the low compliance seen with even the use of the very popular transdermal testosterone gels: only 31% and 14% of patients remain on therapy for 6 months and 1 year, respectively.18 Therefore, the importance of testosterone treatment adherence and patient education should be underscored in clinical practice.

In particular, this study gives further evidence against denying men with obvious symptoms testosterone therapy testosterone therapy because they have "normal" testosterone levels.11 Due to excessive reliance on laboratory measures of testosterone levels and inappropriate safety concerns, many men who could greatly benefit from symptom relief and improvement in risk factors remain untreated and deprived of clinically significant preventive medical benefits.

References

1. Carruthers M, Cathcart P, Feneley MR. Evolution of testosterone treatment over 25 years: symptom responses, endocrine profiles and cardiovascular changes. The aging male : the official journal of the International Society for the Study of the Aging Male. 2015;Published online July 28, 2015.
2. Bernie AM, Scovell JM, Ramasamy R. Comparison of questionnaires used for screening and symptom identification in hypogonadal men. The aging male : the official journal of the International Society for the Study of the Aging Male. 2014;17(4):195-198.
3. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
4. Kelleher S, Conway AJ, Handelsman DJ. Blood testosterone threshold for androgen deficiency symptoms. J Clin Endocrinol Metab. 2004;89(8):3813-3817.
5. Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab. 2006;91(11):4335-4343.
6. Carruthers M, Trinick TR, Wheeler MJ. The validity of androgen assays. The aging male : the official journal of the International Society for the Study of the Aging Male. 2007;10(3):165-172.
7. Moreno SA, Shyam A, Morgentaler A. Comparison of free testosterone results by analog radioimmunoassay and calculated free testosterone in an ambulatory clinical population. The journal of sexual medicine. 2010;7(5):1948-1953.
8. Carruthers M. The paradox dividing testosterone deficiency symptoms and androgen assays: a closer look at the cellular and molecular mechanisms of androgen action. The journal of sexual medicine. 2008;5(4):998-1012.
9. Behre HM, Nieschlag E. Testosterone preparations for clinical use in males. In Nieschlag E, Behre HM, (Eds). Testosterone - Action, Deficiency, Substitution 2012:309-335.
10. Giagulli VA, Triggiani V, Corona G, et al. Evidence-based medicine update on testosterone replacement therapy (TRT) in male hypogonadism: focus on new formulations. Curr Pharm Des. 2011;17(15):1500-1511.
11. Carruthers M, Cathcart P, Feneley MR. Evolution of testosterone treatment over 25 years: symptom responses, endocrine profiles and cardiovascular changes. The aging male : the official journal of the International Society for the Study of the Aging Male. 2015:1-11.
12. 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. J Androl. 2009;30(1):1-9.
13. Dohle GR, Arver S, Bettocchi C, et al. EAU Guidelines on Male Hypogonadism. European Association of Urology 2012.
14. Morales A, Spevack M, Emerson L, et al. Adding to the controversy: pitfalls in the diagnosis of testosterone deficiency syndromes with questionnaires and biochemistry. The aging male : the official journal of the International Society for the Study of the Aging Male. 2007;10(2):57-65.
15. Miwa Y, Kaneda T, Yokoyama O. Correlation between the Aging Males' Symptoms Scale and sex steroids, gonadotropins, dehydroepiandrosterone sulfate, and growth hormone levels in ambulatory men. The journal of sexual medicine. 2006;3(4):723-726.
16. Black AM, Day AG, Morales A. The reliability of clinical and biochemical assessment in symptomatic late-onset hypogonadism: can a case be made for a 3-month therapeutic trial? BJU Int. 2004;94(7):1066-1070.
17. Maganty A, Shoag JE, Ramasamy R. Testosterone threshold - does one size fit all? The aging male : the official journal of the International Society for the Study of the Aging Male. 2015;18(1):1-4.
18. Schoenfeld MJ, Shortridge E, Cui Z, et al. Medication adherence and treatment patterns for hypogonadal patients treated with topical testosterone therapy: a retrospective medical claims analysis. The journal of sexual medicine. 2013;10(5):1401-1409.
Last updated: 2017
G.GM.MH.04.2015.0334