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Hypogonadism is a serious chronic condition associated with chronic comorbidities. What considerations would affect a patient’s long-term adherence to and persistence with testosterone therapy?
Response by Ronald S. Swerdloff, MD

Diagnosing hypogonadism in men can be challenging, especially because signs and symptoms are nonspecific and affected by age, comorbidities, illness, and duration of androgen deficiency.1 Androgens have a profound effect on quality of life,2 and hypogonadism may cause or be associated with diminished libido, progressive decrease in muscle mass, increased body fat and body mass index (BMI), decreased bone density, diminished work performance, depressed mood, and fatigue.1,3,4

Many comorbid conditions are associated with hypogonadism in men. Low levels of testosterone (<11 nmol/L) are associated with a higher risk of diabetes.5 An independent inverse association between testosterone levels and severe atherosclerosis has been demonstrated,6 and low testosterone may be a predictive marker for cardiovascular disease (CVD).7,8 The prevalence rates of hypertension and obesity are significantly higher in hypogonadal men,4 as are significantly elevated serum lipids (eg, low-density lipoproteins, triglycerides).9 Low total testosterone is associated with a greater risk of metabolic syndrome developing over time, especially for nonoverweight (BMI <25), middle-aged men.8

Low testosterone has been shown to precede elevated levels of insulin, glucose, and glycosylated hemoglobin and may be a risk factor for the onset of diabetes.10 During a 10- to 15-year interval, low testosterone was demonstrated to precede the development of central obesity, metabolic syndrome, and diabetes in nonobese men without these conditions at baseline.11

In addition, low serum testosterone has been correlated with a higher mortality rate in older men.11 Laughlin et al demonstrated that total testosterone levels below 241 ng/dL were associated with a 40% higher mortality rate, independent of age, obesity, and lifestyle.

Testosterone therapy is recommended to relieve the symptoms of hypogonadism and to improve quality of life and overall health of men.1 Testosterone therapy also has the potential to slow or stop the progression from metabolic syndrome to CVD or diabetes through improved insulin regulation, lipid profile, and blood pressure.12 Though more data are required to clarify the association, it also has been suggested that testosterone protects the brain from Alzheimer’s disease and improves cognitive function, including memory.13,14

Although taking medication regularly is essential for successful treatment of chronic comorbid conditions such as hypertension, patients may not adhere to treatment, and physicians often inaccurately assess their patients’ adherence.15,16 More effective behavioral strategies to encourage patient adherence are needed.16

Response by Robert S. Tan, MD
Nonadherence to medication is a significant issue for patients with chronic conditions, such that 30% to 50% of patients are not taking their medications as prescribed.17 A significant proportion of patients who initiate treatment with a chronic medication quickly become nonadherent, often intentionally, because of complaints about their medication or lack of information.17 Medication nonadherence should be assessed regularly, with clinicians communicating to patients different routines or behaviors to improve adherence and optimize treatment outcomes.18 For instance, asking the patient to record his medication use in a diary may improve adherence, as would a reminder system for follow-up. Proactively scheduling the patient to return to his physician’s office as a requisite for a medication refill creates another opportunity for follow-up, assessment of treatment efficacy, and safety surveillance.

Involving patients in the decision-making process (eg, regarding the type of testosterone preparation) is essential to promote optimal adherence to testosterone therapy, which is long-term.2,19 Before initiating testosterone therapy, treatment benefits and safety should be communicated to the patients. Adherence to and persistence with long-term testosterone therapy also improves with pharmaceutical formulations that are convenient to use and relatively independent of medical services.20

Long-acting testosterone therapy is available in several formulations, including implants and injections.1,21 Subcutaneous testosterone pellets restore testosterone to physiologic levels over a 4- to 6-month period, however, insertion requires a minor surgical procedure that may be associated with infection and high extrusion rates.22,23

The novel long-acting testosterone undecanoate (TU) intramuscular injection provides a sustained, consistent physiologic level of serum testosterone and is safe and well tolerated.24 Though TU has not yet been approved by the US Food and Drug Administration, a new drug application was submitted in August 2007 and a response submission was filed in March 2009.25 Based on the medication’s long duration of action, the dosing interval for TU is an extended 10 weeks, an improvement over current injectable therapies that require dosing every 2 to 3 weeks and more convenient and perhaps preferable to daily application of transdermal testosterone gels or patches.24 The convenience of fewer injections associated with TU treatment may lead to improved patient adherence to testosterone therapy.24

When choosing a testosterone therapy, the patient’s needs and preference should be considered, as well as the efficacy, safety, tolerability, and pharmacokinetic profile of the formulation and ease and convenience of administration.1 It is important to communicate to the patient that nonadherence to testosterone therapy may impair sexual function, reduce muscle and bone mass, and negatively affect overall quality of life.2

References

  1. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2006;91(6):1995-2010.
  2. Gooren LJG, Bunck MCM. Androgen replacement therapy: present and future [review]. Drugs. 2004;64(17):1861-1891.
  3. Tan RS. Novel treatment options for overlapping yet distinct erectile dysfunction and andropause syndromes. Curr Opin Investig Drugs. 2003;4(4):435-438.
  4. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60(7):762-769.
  5. Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. 2004;27(5):1036-1041.
  6. Hak AE, Witteman JCM, deJong FH, Geerlings MI, Hofman A, Pols HAP. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. J Clin Endocrinol Metab. 2002;87(8):3632-3639.
  7. Khaw KT, Dowsett M, Folkerd E, et al. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European Prospective Investigation Into Cancer in Norfolk (EPIC-Norfolk) prospective population study. Circulation. 2007;116(23):2694-2701.
  8. Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, McKinlay JB. Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J Clin Endocrinol Metab. 2006;91(3):843-850.
  9. Oppenheim DS, Greenspan SL, Zervas NT, Schoenfeld DA, Klibanski A. Elevated serum lipids in hypogonadal men with and without hyperprolactinemia. Ann Intern Med. 1989;111(4):288-292.
  10. Traish AM, Saad F, Guay A. The dark side of testosterone deficiency, II. type 2 diabetes and insulin resistance. J Androl. 2009;30(1):23-32.
  11. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93(1):68-75.
  12. Makhsida N, Shah J, Yan G, Fisch H, Shabsigh R. Hypogonadism and metabolic syndrome: implications for testosterone therapy. J Urol. 2005;174(3):827-834.
  13. Tan RS, Pu SJ. A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer’s disease. Aging Male. 2003;6(1):13-17.
  14. Fuller SJ, Tan RS, Martins RN. Androgens in the etiology of Alzheimer’s disease in aging men and possible therapeutic interventions. J Alzheimers Dis. 2007;12(2):129-142.
  15. Zeller A, Taegtmeyer A, Martina B, Battegay E, Tschudi P. Physicians’ ability to predict patients’ adherence to antihypertensive medication in primary care. Hypertens Res. 2008;31(9):1765-1771.
  16. Lai WA, Chie WC, Lew-Ting CY. How diabetic patients’ ideas of illness course affect non-adherent behaviour: a qualitative study. Br J Gen Pract. 2007;57(537):296-302.
  17. Barber N, Parsons J, Clifford S, Darracott R, Horne R. Patients’ problems with new medication for chronic conditions. Qual Saf Health Care. 2004;13(3):172-175.
  18. Ho PM, Magid DJ, Masoudi FA, McClure DL, Rumsfeld JS. Adherence to cardioprotective medications and mortality among patients with diabetes and ischemic heart disease. BMC Cardiovasc Disord. 2006;6:48-56.
  19. Gooren LJ. Advances in testosterone replacement therapy. Front Horm Res. 2009;37:32-51.
  20. Gooren LJ. New long-acting androgens. World J Urol. 2003;21(5):306-310.
  21. AACE Hypogonadism Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients—2002 update. Endocr Pract. 2002;8(6):439-456.
  22. Harle L, Basaria S, Dobs AS. Nebido: a long-acting injectable testosterone for the treatment of male hypogonadism. Expert Opin Pharmacother. 2005;6(10):1751-1759.
  23. Korbonits M, Slawik M, Cullen D, et al. A comparison of a novel testosterone bioadhesive buccal system, Striant, with a testosterone adhesive patch in hypogonadal males. J Clin Endocrinol Metab. 2004;89(5):2039-2043.
  24. Morgentaler A, Dobs AS, Kaufman JM, et al. Long acting testosterone undecanoate therapy in men with hypogonadism: results of a pharmacokinetic clinical study. J Urol. 2008;180(6):2307-2313.
  25. FDA accepts complete response submission to new drug application for Nebido® [press release]. Chadds Ford, PA: Endo Pharmaceuticals Inc; March 12, 2009.

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