Hypogonadism in men, or androgen deficiency, is a chronic condition characterized by a failure of the testes to produce physiologically normal levels of serum testosterone. The lower limit for normal testosterone levels is usually considered to be 280 ng/dL to 300 ng/dL (definite ranges are laboratory specific due to lack of standardized testing), and anything below this level is considered low.1 The diagnosis of hypogonadism is based on both the presence of visible symptoms of low testosterone and clinical measurement of serum testosterone levels.1 Common symptoms of hypogonadism in men include erectile dysfunction, poor libido, fatigue, decreased muscle mass and strength, decreased bone mass and increased body fat.2,3
Hypogonadism can be primary or secondary, depending on the cause of low testosterone levels. Primary hypogonadism is more prevalent and is caused by a problem with testosterone production within the testes.1 Secondary hypogonadism is caused by a problem outside the testes, usually within the pituitary or hypothalamus, and it reduces stimulus of the testes to produce testosterone.1,2 Serum testosterone levels decrease with age.2 Consequently, androgen deficiency most often occurs in older men (ages 40 to 69) and is referred to as late-onset hypogonadism.
It is difficult to determine the true prevalence of androgen deficiency. Estimates vary widely depending on the study. In the United States, epidemiologic studies have estimated the prevalence at 6% to 12% among men ages 40 to 694 and 38.7% among men 45 and older.5 With the aging demographic in the western world, these numbers are expected to grow. A corresponding impact on health and quality of life will occur.
Perhaps the main problem with treating hypogonadism is that it is often undiagnosed. Apparent symptoms are treated rather than the underlying condition. In addition, many of the symptoms commonly reported with hypogonadism can be considered a normal part of the aging process, so treatment is not initiated despite the potential negative implications for the patient. Because of this, nurse practitioners and physician assistants should be vigilant about including hypogonadism in the differential diagnosis list when men present with symptoms of low testosterone. The diagnostic process should include a review of the patient's medical history and a physical examination to identify signs and symptoms. The assessment should also cover a patient's social history, lifestyle problems, nutritional intake and medication history.
Development of a genogram to chart chronic family illnesses can be useful. To determine if low testosterone symptoms are present, the clinician should screen patients with the Androgen Deficiency in Aging Men (ADAM) questionnaire.
Benefits and Risks of Therapy
Testosterone replacement therapy (TRT) using a synthetic androgen has been available for the treatment of hypogonadism for a number of years. It has proven to be an effective treatment that ameliorates symptoms of low testosterone.3,6,7 TRT has been linked to the improvement of other health conditions associated with low testosterone levels, for example type 2 diabetes. Studies in patients with hypogonadism and type 2 diabetes have reported a beneficial effect of TRT on glycemic control, insulin resistance and cholesterol levels.6,8 Treating low testosterone with TRT may decrease cardiovascular risks through moderation of many metabolic factors associated with cardiovascular risk.9 In addition, increasing testosterone levels can have a positive impact on memory and cognition.10
Rather than a blanket treatment for all men with low testosterone levels, guidelines recommend TRT to treat specific symptoms of hypogonadism. In particular, guidelines published by the Endocrine Society recommend TRT in symptomatic, androgen-deficient men to improve their sexual function, sense of well-being and bone mineral density.1
A number of contraindications and concerns should be considered before deciding if therapy is appropriate (Table 1). TRT is contraindicated in men with breast cancer or suspected prostate cancer, although the risk of stimulating prostate cancer through TRT appears to be low.11 Consensus recommendations from the International Society of Andrology, the International Society for the Study of the Aging Male, the European Association of Urology, the European Academy of Andrology and the American Society of Andrology state that there is no evidence testosterone treatment increases the risk of prostate cancer or benign prostatic hyperplasia, or that treatment will convert subclinical prostate cancer to clinically detectable prostate cancer.2 However, these organizations do recommend that hypogonadal older men should be counseled about the risks and benefits of TRT and should be monitored for serum testosterone levels and prostate safety throughout treatment.2 In contrast, the American Association of Clinical Endocrinologists states that TRT can stimulate tumor growth in androgen-dependent neoplasms and cautions against the use of TRT in men with prostate cancer.2
Other issues associated with the use of TRT include: liver toxicity; exacerbation of benign prostatic hypertrophy; worsening of untreated sleep apnea; heart failure in patients with pre-existing cardiac, renal or hepatic disease; polycythemia; and unintentional exposure of women and children to testosterone via topical TRT. Guidelines recommend that healthcare professionals periodically monitor specific lab values in patients taking TRT (Table 2).2 In addition to this, NPs and PAs should periodically collect social and voiding histories, assess sleep patterns and muscle strength, and perform a digital rectal examination.
Due to the chronic nature of hypogonadism and the need for long-term therapy, patient preference is an important factor in treatment selection. The challenge is in providing an effective treatment that elevates testosterone levels to within the normal range (usually a target range of 400 ng/dL to 700 ng/dL)1 and quickly alleviates symptoms with minimal impact on patients' daily lives.
TRT therapies are available in a number of formulations, including buccal applications, intramuscular injections, subdermal implants, transdermal patches, topical solutions and gels (Table 2). Details are outlined in the sections below.
A buccal formulation of testosterone (Striant) has been proven effective in normalizing serum testosterone levels, with 72.6% of patients reaching mean 24-hour testosterone levels within the normal range.12 Despite the efficacy, uptake of this treatment has been low due in part to some patients experiencing difficulty placing the buccal tablet on the gums or experiencing gum or mouth irritation or tenderness. The medication requires twice-daily dosing, which can be inconvenient for patients.
The first TRT therapies to be developed, and still among the most widely used, are intramuscular injections of testosterone esters. These are currently available in the United States as the relatively short-term formulations testosterone cypionate and testosterone enanthate. Both are generally administered as an injection once every 2 weeks.
The main drawback with these treatment options is the pharmacokinetic profile of the esters. These products produce more severe peaks and troughs in serum testosterone levels than other TRT preparations.13 In addition, while the longer duration of exposure from these products compared with buccal and transdermal applications may be convenient for the patient (i.e., longer periods between doses), it also means that testosterone levels will take longer to return to baseline if the treatment needs to be discontinued.
Testosterone undecanoate injection, which is also administered as an intramuscular injection, is in development by Endo Pharmaceuticals but as of press time in January 2013, it had not been approved by the Food and Drug Administration.14 Unlike testosterone esters, testosterone undecanoate maintains an even testosterone delivery within the normal range for 10 to 14 weeks. If cleared for marketing, this TRT would provide an additional option for patients who require an alternative to topical therapies and who would prefer extended periods between treatment administrations. As with previous intramuscular injections, the longer duration of exposure compared with buccal and transdermal applications means that testosterone levels take longer to return to baseline if the treatment needs to be discontinued for any reason.
Subcutaneous Testosterone Implant
Another long-acting TRT formulation is a subcutaneous testosterone implant (Testopel). The main benefit of this formulation from the patient perspective is its long duration of action: 2 to 6 pellets are administered parenterally every 3 to 6 months. However, the implants carry a risk of infection, and extrusion of the pellets through the skin occurs with some regularity. In addition, the requirement for surgical implantation and removal of the pellets may be a significant barrier to patient acceptance.
Transdermal Testosterone Therapy
Although topical testosterone formulations have been available for a number of years, recent developments have increased the range of treatment options. Three delivery mechanisms are used for topical testosterone therapy today: patches, solutions and gels.
Testosterone patches contain a reservoir of testosterone. These adhesive devices can be applied to scrotal or nonscrotal skin, depending on the product. They are designed to be applied once daily. In addition to being simple to apply and avoiding the need for injections, testosterone patches maintain serum testosterone at a much steadier level than that provided by short-acting testosterone ester injections. Compared with gels, patches have a reduced potential for accidental transfer of testosterone to others. However, patches have been associated with a high incidence of application site reactions and skin irritation.13
Gel formulations provide an alternative to testosterone patches. Until 2010, only two testosterone gels were approved for use in the United States, Androgel and Testim. These products contain a 1% testosterone concentration in a metered-dose (1.25 g) pump, packet (2.5 or 5 g) or tube (5 g).
Three new transdermal treatments have become available in the past 2 years. These products, two gel formulations and one testosterone solution, contain a higher percentage of testosterone per gram so they decrease the volume of product required with each application. For example, 2% testosterone gel (Fortesta) is packaged in a metered-dose canister, allowing testosterone doses to be titrated in 10-mg intervals from 10 mg to 70 mg.15 This is the smallest dosing interval of any gel or solution, permitting the greatest dose flexibility. The other recently approved treatment is a 1.62% testosterone gel (Androgel 1.62%). This is a version of the currently marketed 1% gel, with a higher testosterone concentration.
Also available is a 2% topical testosterone solution designed for application to the underarm (Axiron).16 As with the other topical formulations, application is once daily. Although this product contains a 2% formulation like the 2% gel, it appears that more medication is necessary to achieve similar results.15 The fluid consistency of the drug can make application difficult for some patients.
For patients and clinicians, the main concerns with all topical gels and solutions are the properties of the formulations (how much drying time is needed, difficulty of application and presence of odor) and the potential for transfer of the treatment from the patient to others.13 Transference is a concern due to the relatively large percentage of testosterone that remains on the surface of the skin for several hours after application. Accidental transfer via skin-to-skin contact with nonhypogonadal people may lead to increased testosterone levels, particularly in women and children.13 Adverse events reported in children include enlargement of the genitalia, premature pubarche, advanced bone age and aggressive behavior.13
Hypogonadism is a chronic condition that can have negative effects on patient health and quality of life. Effective TRT therapies are available to restore serum testosterone levels to the normal range. The variety of delivery methods allows patient preference to be considered in order to maximize adherence and provide the most effective treatment possible.
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1. Bhasin S, 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.
2. Wang C, et al. ISA, ISSAM, EAU, EAA and ASA recommendations: Investigation, treatment and monitoring of late-onset hypogonadism in males. Int J Impot Res. 2009;21(1):1-8.
3. Rolf C, et al. Testosterone substitution of hypogonadal men prevents the age-dependent increases in body mass index, body fat and leptin seen in healthy ageing men: results of a cross-sectional study. Eur J Endocrinol. 2002;146(4):505-511.
4. Araujo AB, et al. Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab. 2004;89(12):5920-5926.
5. Mulligan T, et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60(7):762-769.
6. Jones TH, et al.; TIMES2 Investigators. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care. 2011;34:828-837.
7. Moncada I. Testosterone and men's quality of life. Aging Male. 2006;9(4):189-193.
8. Kapoor D, et al. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006;154(6):899-906.
9. Corona G, et al. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur J Endocrinol. 2011;165(5):687-701.
10. Martin DM, et al. Testosterone and cognitive function in ageing men: data from the Florey Adelaide Male Ageing Study (FAMAS). Maturitas. 2007;57(2):182-194.
11. Rhoden EL, Averbeck MA. Testosterone therapy and prostate carcinoma. Curr Urol Rep. 2009;10(6):453-459.
12. Wang C, et al. New testosterone buccal system (Striant) delivers physiological testosterone levels: pharmacokinetics study in hypogonadal men. J Clin Endocrinol Metab. 2004;89(8):3821-3829.
13. Lakshman KM, Basaria S. Safety and efficacy of testosterone gel in the treatment of male hypogonadism. Clin Interv Aging. 2009;4:397-412.
14. Wang C, et al. Pharmacokinetics of long-acting testosterone undecanoate injections in hypogonadal men: an 84-week phase III clinical trial. J Androl. 2010;31(5):457-465.
15. Dobs A, et al. A novel testosterone 2% gel for the treatment of hypgonadal males. J Androl. 2012;33(4):601-607.
16. Wang C, et al. Efficacy and safety of the 2% formulation of testosterone topical solution applied to the axillae in androgen-deficient men. Clin Endocrinol. 2011;75(6):836-843.
Demetrius Porche is a family nurse practitioner who is dean of the Louisiana State University (LSU) Health Sciences Center School of Nursing in New Orleans. Todd Tartavoulle is a clinical nurse specialist who is an instructor in the LSU Health Sciences Center School of Nursing. The authors have completed disclosure statements and report that they received writing assistance from Watermeadow Medical. This assistance was supported by Endo Pharmaceuticals.