What is the evaluation and management of hypogonadism in elderly men?

Submitted by Craig Comiter, MD

Response by Carol Howe, MD, MLS

The primary difficulty of diagnosing hypogonadism in elderly men is the fact that many of the symptoms progress so gradually as to be almost imperceptible and also correspond with many of the symptoms attributed to aging in general. “The effect of T [testosterone] on the central nervous system extends beyond sexual behavior. T has been shown to alter mood, memory, ability to concentrate, and the overall sense of vigor and well being that may interact with a host of other psychologic changes associated with aging” (Mooradian & Korenman, 2006, abstract). “Symptoms and findings of testosterone deficiency are similar to those associated with aging. They include loss of energy, depressed mood, decreased libido, erectile dysfunction, decreased muscle mass and strength, increased fat mass, frailty, osteopenia, and osteoporosis” (Hijazi & Cunningham, 2005, abstract). “Such age-associated T deficiency, which has been termed 'andropause', is thought to be responsible for a variety of symptoms experienced by elderly men, such as weakness, fatigue, reduced muscle and bone mass, impaired haematopoiesis, oligospermia, sexual dysfunction, depression, anxiety, irritability, insomnia and memory impairment” (Seidman, 2003, abstract).

After studying recommendations from “An International Consultation in collaboration with the major urology and sexual medicine associations [which] assembled over 200 multidisciplinary experts from 60 countries into 17 committees” (Morales et al, 2004, abstract), Morales et al summarize that

Hypogonadism is a clinical and biochemical syndrome characterized by a deficiency in serum androgen levels which may decrease sexual interest, quality of erections and quality of life. Biochemical investigations include testosterone and either bioavailable or calculated free testosterone; prolactin should be considered when hypogonadism has been documented. If clinically indicated, androgen therapy should maintain testosterone within the physiological range avoiding supraphysiologic values. Digital rectal examination and determination of serum prostate specific antigen values are mandatory prior to therapy and regularly thereafter. Androgen therapy is usually long-term requiring regular follow-up, frequent monitoring of blood levels and beneficial and adverse therapeutic responses. (abstract)

Makshida et al (2006) found a fascinating correlation between hypogonadism and metabolic disease and, in fact, suggest that hypogonadism may be one of metabolic syndrome’s central attributes along with obesity, insulin resistance, hypertension and hyperlipidemia. They conclude:

Hypogonadism is likely a fundamental component of metabolic syndrome. Testosterone therapy may not only treat hypogonadism, but may also have tremendous potential to slow or halt the progression from metabolic syndrome to overt diabetes or cardiovascular disease via beneficial effects on insulin regulation, lipid profile and blood pressure. Furthermore, the use of testosterone to treat metabolic syndrome may also lead to the prevention of urological complications commonly associated with these chronic disease states, such as neurogenic bladder and erectile dysfunction. (abstract)

Thus, where other authors stress the fact that erectile function may not necessarily reflect hypogonadism so much as vascular, neurologic or psychogenic disease  (see Mooradian and Koreman abstract), Makshida et al actually bring it full circle in showing, for example that vascular or neurologic disease—felt to be causing sexual dysfunction-- may share the same underlying disorder (metabolic syndrome) as hypogonadism.

While these authors are enthusiastic about testosterone replacement, many others caution against overenthusiastic prescribing of testosterone. Hijazi & Cunningham (2005), for example, note that:

Several small clinical trials indicate that testosterone replacement therapy can improve many of these findings; however, the studies have not been powered to assess potential risks, such as the need for invasive treatment of benign prostatic hyperplasia, development of a clinical prostate cancer, or cardiovascular events. Thus, the benefit/risk ratio of testosterone replacement therapy in aging men is not known. (abstract)

Kaufman and Vermeulen (2005) in their article, “The decline of androgen levels in elderly men and its clinical and therapeutic implications,” note that “the clinical picture of aging in men is reminiscent of that of hypogonadism in young men” (abstract), but that androgen levels in elderly men are widely variable and their significance thus far has been inadequately studied and are therefore poorly understood.

In fact, minimal androgen requirements for elderly men remain poorly defined and are likely to vary between individuals. Consequently, borderline androgen deficiency cannot be reliably diagnosed in the elderly, and strict differentiation between "substitutive" and "pharmacological" androgen administration is not possible. To date, only a few hundred elderly men have received androgen therapy in the setting of a randomized, controlled study, and many of these men were not androgen deficient. Most consistent effects of treatment have been on body composition, but to date there is no evidence-based documentation of clinical benefits of androgen administration to elderly men with normal or moderately low serum testosterone in terms of diminished morbidity or of improved survival or quality of life. (abstract)

Screening/ Diagnosis of Hypogonadism

Morales et al (2004) have a nice summary of diagnostic measures used to diagnose hypogonadism. This includes a summary of clinical features, a discussion of the various screening questionnaires and a discussion of the difficulties inherent in the various serum tests. Some of the latter include:

1. Confounding caused by active metabolites when testosterone is metabolized within tissues.
2. “Interindividual differences in androgen sensitivity” (p.74).
3. The natural increase in sex hormone binding globulin (SHBG) with age “which translates to a decrease in bioavailable [free and albumin-bound fractions] testosterone.
4. A ”flattening of the circadian rhythm leading to steady low levels of androgens throughout the 24 hour cycle” (p74).

Morales et al note that free testosterone “provides a more reliable index of androgenicity” (p.75) and, although they mention some of the difficulties with particular assays, do state that the ammonium sulphate precipitation method is generally “more commonly accessible, reliable, and less expensive” (p. 75). They refer the reader to the Free & Bioavailable Testosterone calculator developed by Vermeulen http://issam.ch/freetesto.htm available from the International Society for the Study of the Aging Male’s website (http://issam.ch/.

Morley et al (2006a) also discuss the convenience (though not superiority) of measuring salivary testosterone as a non-invasive way to screen for hypogonadism. Morley et al (2006b) compared the usefulness of three different screening questionnaires, the St. Louis University Androgen Deficiency in Aging Male (ADAM), the Aging Male Survey (AMS) and the Massachusetts Male Aging Study (MMAS). In general they found that some of the questions were well correlated with bioavailable testosterone and calculated free testosterone but not with total testosterone. They found the ADAM and the AMS questionnaires to be sensitive but not specific. The MMAS was neither sensitive nor specific.

Black et al (2004) did a small study (n of 38 males who actually completed the study) in which they studied the effects of a 3-month therapeutic trial. They undertook this precisely because of the difficulties in actually pinning down a diagnosis of symptomatic late-onset hypogonadism (SLOH). Theirs conclusions to what was essentially a pilot study was that “this controversial position needs further evaluation with a larger cohort and other biochemical measurements” (abstract).

Snyder, in his 2004 New England Journal of Medicine “Perspective” piece reminds us that “An essential but still unanswered question is whether this decrease in the testosterone concentration is physiologic, perhaps conveying a benefit, or pathologic, causing harm” (p.441).

Another essential, but also unanswered, question is whether reversing this decrease in testosterone concentrations will exacerbate the testosterone-dependent diseases to which elderly men are prone, including prostate cancer, benign prostatic hyperplasia, erythrocytosis, and perhaps sleep apnea. No data, unfortunately, are available with which to answer this question. (p. 441)

Snyder proceeds to discuss the Institute of Medicine Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy’s report, Testosterone and aging: clinical research directions. The authors of this report, according to Snyder, actually do not even feel that 

a long-term study to determine the risks associated with testosterone replacement [is presently warranted].  Instead, the committee recommended first performing short-term, randomized, placebo-controlled studies of the effect of testosterone on several outcomes in elderly men whose testosterone concentrations are below 300 ng per deciliter and then, only if the short-term studies demonstrate efficacy, performing a long-term study to evaluate the risks. (p. 441)

Snyder then outlines four basic principles to help guide practicing physicians in the interim period. In brief these are:

• The criteria for establishing a diagnosis of hypogonadism should be “more stringent in the absence than in the presence of a disease that is known to cause hypogonadism, such as a pituitary macroadenoma, and should be more stringent in an elderly man — say, older than 65 years of age — than in a younger man” (p. 442).
• “To limit treatment to men who are more severely hypogonadal, on the premise that those men are more likely to benefit” (p.442)
• Serum testosterone levels need to be very carefully monitored in patients receiving replacement therapy.
• “To screen for testosterone-dependent diseases before initiating treatment and to monitor patients for their development during treatment” (p.442).

In summary, there is a clear dearth of evidence -based studies that seek to clarify the evaluation and treatment of hypogonadism in elderly males. Reviewing even the abstracts of the articles listed in the references provided demonstrates multiple opinions about whether there even is a clinical syndrome of hypogonadism; what the features of that clinical syndrome are; the appropriate lab tests to order to help in diagnosis (many authors refer to free or bioavailable testosterone as the gold standard while others, for example Snyder [2004] hold that assays for total testosterone are much more reliable and available than assays for free testosterone); whether testosterone therapy is effective in alleviating symptoms; whether testosterone therapy is safe (careful monitoring for prostate malignancies and a contraindication to its use in men with a history of prostate cancer is advocated by most--  some, however, such as Rhoden and Morgentaler  [2003]--conclude: “After 1 year of TRT men with PIN do not have a greater increase in PSA or a significantly increased risk of cancer than men without PIN. These results indicate that TRT is not contraindicated in men with a history of PIN, [abstract].”  It is interesting, though not surprising, to note that I did not find any articles advocating for or against routine screening of hypogonadism is elderly men. Given the controversies at each level, the issue of screening would seem to be a true Pandora’s box.

In the presence of such a complete lack of consensus on any aspect of definition, evaluation and treatment, it does indeed seem puzzling that more definitive studies were not recommended by the Institute of Medicine’s Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy. I can only agree with Snyder’s (2004) implication and Harman’s (2005) frank assertion that the committee’s “recommendation, if adhered to, is likely to delay, rather than foster, progress in this important area” (abstract).

References

Black, A. M., Day, A. G., & Morales, A. (2004). The reliability of clinical and biochemical assessment in symptomatic late-onset hypogonadism: Can a case be made for a 3-month therapeutic trial? BJU international, 94(7), 1066-1070.

Free & Bioavailable Testosterone calculator     http://issam.ch/freetesto.htm

Gruenewald, D. A., & Matsumoto, A. M. (2003). Testosterone supplementation therapy for older men: Potential benefits and risks. Journal of the American Geriatrics Society, 51(1), 101-15; discussion 115.

Harman, S. M. (2005). Testosterone in older men after the institute of medicine report: Where do we go from here? Climacteric : the journal of the International Menopause Society, 8(2), 124-135.

Hijazi, R. A., & Cunningham, G. R. (2005). Andropause: Is androgen replacement therapy indicated for the aging male? Annual Review of Medicine, 56, 117-137.

Isidori, A. M., Greco, E. A., & Aversa, A. (2005). Androgen deficiency and hormone-replacement therapy. BJU international, 96(2), 212-216.

International Society for the Study of the Aging Male   http://issam.ch/ 

Kaufman, J. M., & Vermeulen, A. (2005). The decline of androgen levels in elderly men and its clinical and therapeutic implications. Endocrine reviews, 26(6), 833-876.

Liverman CT, Blazer DG, (Eds.) (2004). Testosterone and aging: clinical research directions. [Electronic Version]. Washington, D.C.: National Academies Press

Makhsida, N., Shah, J., Yan, G., Fisch, H., & Shabsigh, R. (2005). Hypogonadism and metabolic syndrome: Implications for testosterone therapy. The Journal of urology, 174(3), 827-834..

Mooradian, A. D., & Korenman, S. G. (2006). Management of the cardinal features of andropause. American Journal of Therapeutics, 13(2), 145-160.

Morales, A., Buvat, J., Gooren, L. J., Guay, A. T., Kaufman, J. M., & Tan, H. M., et al. (2004). Endocrine aspects of sexual dysfunction in men. The journal of sexual medicine, 1(1), 69-81.

Morales, A., Lunenfeld, B., & International Society for the Study of the Aging Male. (2002). Investigation, treatment and monitoring of late-onset hypogonadism in males. official recommendations of ISSAM. international society for the study of the aging male. The aging male: the official journal of the International Society for the Study of the Aging Male, 5(2),74-86.

Morley, J. E., Perry, H. M.,3rd, Kevorkian, R. T., & Patrick, P. (2006). Comparison of screening questionnaires for the diagnosis of hypogonadism. Maturitas, 53(4), 424-429.

Morley, J. E., Perry, H. M.,3rd, Patrick, P., Dollbaum, C. M., & Kells, J. M. (2006). Validation of salivary testosterone as a screening test for male hypogonadism. The aging male : the official journal of the International Society for the Study of the Aging Male, 9(3), 165-169.

Nieschlag, E., Swerdloff, R., Behre, H. M., Gooren, L. J., Kaufman, J. M., & Legros, J. J., et al. (2005). Investigation, treatment and monitoring of late-onset hypogonadism in males. The aging male : the official journal of the International Society for the Study of the Aging Male, 8(2), 56-58.

Rhoden, E. L., & Morgentaler, A. (2003). Testosterone replacement therapy in hypogonadal men at high risk for prostate cancer: Results of 1 year of treatment in men with prostatic intraepithelial neoplasia. The Journal of urology, 170(6 Pt 1), 2348-2351.

Schubert, M., & Jockenhovel, F. (2005). Late-onset hypogonadism in the aging male (LOH): Definition, diagnostic and clinical aspects. Journal of endocrinological investigation, 28(3 Suppl), 23-27.

Seftel, A. D. (2006). Male hypogonadism. part I: Epidemiology of hypogonadism. International Journal of Impotence Research, 18(2), 115-120.

Seidman, S. N. (2003). The aging male: Androgens, erectile dysfunction, and depression. The Journal of clinical psychiatry, 64 Suppl 10, 31-37.

Seidman, S. N. (2003). Testosterone deficiency and mood in aging men: Pathogenic and therapeutic interactions.: the official journal of the World Federation of Societies of Biological Psychiatry, 4(1), 14-20.

Snyder, P. J. (2004). Hypogonadism in elderly men--what to do until the evidence comes. The New England journal of medicine, 350(5), 440-442.

Tenover, J. S. (2003). Declining testicular function in aging men. International Journal of Impotence Research, 15 Suppl 4, S3-8.

Tsujimura, A., Matsumiya, K., Matsuoka, Y., Takahashi, T., Koga, M., & Iwasa, A., et al. (2003). Bioavailable testosterone with age and erectile dysfunction. The Journal of urology, 170(6 Pt 1), 2345-2347.

Vermeulen, A., & Kaufman, J. M. (2002). Diagnosis of hypogonadism in the aging male. The aging male : the official journal of the International Society for the Study of the Aging Male, 5(3), 170-176.

Wang, C., & Swerdloff, R. S. (2005). Pratical aspects of testosterone substitution. Journal of endocrinological investigation, 28(3 Suppl), 109-111.