Current approaches to hypogonadism in primary care: How to help the aging male? "Beyond the Abstract," by Bruno Lunenfeld and Stefan Arver

BERKELEY, CA (UroToday.com) - Hypogonadism is a common condition in men, and is more frequent in older men (late-onset hypogonadism (LOH)), however it continues to be under-recognized and undertreated by physicians. The prevalence of hypogonadism increases with age, as circulating testosterone (T) in men progressively diminishes from the third decade.[1, 2, 3] Thus, as populations show increased aging, hypogonadism is likely to become more common, with physicians increasingly likely to encounter the syndrome in the clinic. Various conditions increase the risk of developing hypogonadism including obesity, cardiovascular disease, diabetes, hypertension, hyperlipidemia, inflammatory/rheumatic disease, asthma or chronic obstructive pulmonary disease, prostate disease,[4] and history of (male) infertility.[5] Conversely, hypogonadism also increases the risk of some of these conditions. Moreover, evidence also associates metabolic syndrome with androgen deficiency.[6]

As diagnosis can be difficult, it is important to avoid hypogonadal symptoms being dismissed as signs of aging because they develop slowly and overlap with other common disorders in older men. Hypogonadism is generally defined as low T levels together with hypogonadal symptoms and signs which can often be nonspecific. While low libido is a common symptom, others include erectile dysfunction, increased body fat (visceral/abdominal), decreased muscle mass and strength, decreased vitality, depressed mood, decreased bone mineral density (BMD), and osteoporosis.[7] Low T can precipitate significant health risks, such as falls and fractures associated with brittle bones and lower muscle strength, and can seriously impair quality of life.

In the absence of uniformly accepted lower limits of normal T, there is general agreement that patients with serum total T (TT) < 8 nmol/l (230 ng/dl) are likely to benefit from T supplementation whereas those with TT >12 nmol/l (350 ng/dl) generally do not need substitution - although in some patients with TT > 12 nmol/l, symptoms may occur[8] and T supplementation may be beneficial.[9,10] The European Male Aging Study showed that LOH can be defined by the occurrence of at least three sexual symptoms (erectile dysfunction, reduced frequency of sexual thoughts, and lower frequency of morning erection) associated with TT < 11 nmol/l (320 ng/dl) and free T < 220 pmol/l[11] - using this definition, the overall prevalence of LOH was calculated at 2.1%. However, the prevalence was appreciably higher in those > 60 years. Diagnosis of hypogonadism should include a medical history and a thorough physical and biochemical examination.[7] Laboratory testing is necessary to confirm a clinical diagnosis and to distinguish between primary (hypergonadotropic) and secondary (hypogonadotropic) hypogonadism. Moreover, potential comorbidities should be investigated as possible causes of symptoms, such as erectile dysfunction, metabolic syndrome, diabetes, obesity, and osteoporosis.

The goal of T therapy is to achieve serum T within the physiological range and to improve symptoms with the aim of reducing disability, enhancing quality of life, and adding life to years.[12] It is important to match the most appropriate treatment to the individual patient. Risks/benefits must be discussed and careful follow-up is needed.[7] Although in locally advanced/metastatic prostate cancer, T supplementation can aggravate symptoms and stimulate tumour proliferation, there is no evidence of increased risk of initiating prostate cancer; nevertheless it is contraindicated in men with prostate cancer or breast cancer.[7] Also, men should not begin T therapy without prior resolution of the following comorbid conditions: untreated obstructive sleep apnea, untreated severe congestive heart failure or significant erythrocytosis (hematocrit >52%).[7]

T supplementation can provide many benefits including improved sexual function, improved body composition (reduced fat mass and/or increased lean body mass), and improved BMD.[7] Potential adverse effects of T supplementation include acne and oily skin, decreased sperm production and infertility, erythrocytosis, male pattern balding (familial), and gynecomastia.[5]

There are several T formulations and administration routes available: gels, injections, patches, implants, tablets, pellets and solutions. Treatment selection should preferably be a shared decision between the physician and an informed patient[7] and can be individualized by taking into account not only patient preference but also issues such as adverse events, dosing, monitoring, and cost.[13] The most commonly used T formulations are gels and injections. While injections benefit from infrequent administration intervals, peak and trough fluctuations in T levels can be a feature of traditional formulations,[5,14] although such fluctuations are avoided with the relatively new T undecanoate injection.[15] Transdermal preparations benefit from their ease of administration and can minimize T fluctuations. However, gels carry a risk of contact transmission to partners/children while patches can be associated with skin irritation at the application site. Benefits of gels include improvements in body composition, BMD of the lumbar spine, and sexual function.[16,17] Gels also benefit from a generally good tolerability profile,[18,19] self-application, ease of dose titration, and speed of drying. Various T gel formulations are available, however, they are not identical and may display differences in bioavailability.[20] Also, patients with a suboptimal response to one T gel may benefit from changing to an alternative brand as observed, for example, in studies of patients switching from AndroGel to Testim.[21, 22, 23]

In conclusion, despite significant advances in understanding the pathophysiology, diagnostic methods and treatment of hypogonadism over the past several decades, it continues to be underdiagnosed and often undertreated. As symptoms of hypogonadism, aging, and other medical disorders can overlap, clinicians should be aware that older men with hypogonadism may present with symptoms that are easily misinterpreted as signs of aging or chronic disease. Barriers to diagnosis and treatment referral in the primary care setting may include inadequate provider knowledge or assessment tools, lack of physician–patient communication, and cultural, personal, or gender influences.[24, 25] As a consequence, primary care physicians, as well as urologists, must be fully aware of how to recognise and treat the condition. An understanding of the monitoring and testing needed, and the advantages and disadvantages of the available T formulations, will also facilitate optimal management of the condition with the aim of devising a therapeutic strategy that best suits patients’ individual requirements. While there is generally consensus on the use of T supplementation for classical hypogonadism, T therapy in non-classical hypogonadism remains controversial and requires consideration on a case-by-case basis. T therapy offers many benefits to hypogonadal men, however, before initiating therapy it is important to discuss with patients the advantages and risks of therapy with full consideration of risk factors including potential prostatic disease.

References:

  1. Wu FC, Tajar A, Pye SR, et al.; European Male Aging Study Group. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab 2008;93:2737–2745.
  2. Gray A, Feldman HA, McKinlay JB, Longcope C. Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study. J Clin Endocrinol Metab 1991;73:1016–1025.
  3. Orwoll E, Lambert LC, Marshall LM, et al. Testosterone and estradiol among older men. J Clin Endocrinol Metab 2006;91:1336–1344.
  4. Mulligan T, Frick MF, Zuraw QC, et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract 2006;60:762–769.
  5. 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;95:2536–2559.
  6. Traish AM, Guay A, Feeley R, Saad F. The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction. J Androl 2009;30:10–22.
  7. Wang C, Nieschlag E, Swerdloff RS, et al. ISA, ISSAM, EAU, EAA and ASA recommendations: investigation, treatment and monitoring of late-onset hypogonadism in males. Aging Male 2009;12:5–12.
  8. Zitzmann M, Faber S, Nieschlag E. Association of specific symptoms and metabolic risks with serum testosterone in older men. J Clin Endocrinol Metab 2006;91:4335–4343.
  9. Behre HM, Tammela TL, Arver S, et al.; for the European Testogel® Study Team®. A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up. Aging Male 2012;15(4):198-207.
  10. Shabsigh R, Kaufman JM, Steidle C, Padma-Nathan H. Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. J Urol 2004;172:658–663.
  11. Wu FC, Tajar A, Beynon JM, et al.; EMAS Group. Identification of late-onset hypogonadism in middle aged and elderly men. N Engl J Med 2010;363:123–135.
  12. Lunenfeld B, Nieschlag E. Testosterone therapy in the aging male. Aging Male 2007;10:139–153.
  13. Brunton SA, Sadovsky R. Late-onset male hypogonadism and testosterone replacement therapy in primary care. J Fam Pract 2010;59:S1–S8.
  14. Miner M, Canty DJ, Shabsigh R. Testosterone replacement therapy in hypogonadal men: assessing benefits, risks, and best practices. Postgrad Med 2008;120:130–153.
  15. Yassin AA, Haffejee M. Testosterone depot injection in male hypogonadism: a critical appraisal. Clin Interv Aging 2007;2:577–590.
  16. Loizides E, Swierzewski MJ, O’Neill C, Griesser J, Smith T. Early Response Time in Sexual Activity and Mood Following Testosterone Gel Replacement in Hypogonadal Males from the Testim® START Study. Rev Urol 2004;6 Suppl 6:S16–S21.
  17. Dean JD, Carnegie C, Rodzvilla J, Smith T. Long-term effects of testim ® 1% testosterone gel in hypogonadal men. Rev Urol 2004;6 Suppl 6:S22–S29.
  18. McNicholas T, Ong T. Review of Testim gel. Expert Opin Pharmacother 2006;7:477–484.
  19. Miner MM, Sadovsky R. Evolving issues in male hypogonadism: evaluation, management, and related comorbidities. Cleve Clin J Med 2007;74 Suppl 3:S38–S46.
  20. Marbury E, Hamill R, Bachand T, Sebree T, Smith T. Evaluation of the pharmacokinetic profiles of the new testosterone topical gel formulation, Testim, compared to AndroGel. Biopharm Drug Dispos 2003;24:115–120.
  21. Grober ED, Khera M, Soni SD, et al. Efficacy of changing testosterone gel preparations (Androgel or Testim) among suboptimally responsive hypogonadal men. Int J Impot Res 2008;20:213–217.
  22. Steidle C, Witt MA, Matrisciano J, Block JE. Sexual functioning and satisfaction in nonresponders to testosterone gel: Potential effectiveness of retreatment in hypogonadal males. Clin Cornerstone 2005;7 Suppl 4:S20–S25.
  23. Schrader S, Mills A, Scheperle M, Block JE. Improvement in sexual functioning and satisfaction in nonresponders to testosterone gel: clinical effectiveness in hypogonadal, HIV-positive males. Clin Cornerstone 2005;7 Suppl 4:S26–S31.
  24. Bhattacharya RK, Khera M, Blick G, Kushner H, Miner MM. Testosterone replacement therapy among elderly males: the Testim Registry in the US (TRiUS). Clinical Interventions in Aging 2012:7 321–330.
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Written by:

Bruno Lunenfelda and Stefan Arverb as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

aFaculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel, bCentre for Andrology and Sexual Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden

How to help the aging male? Current approaches to hypogonadism in primary care - Abstract

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