Prescribing Testosterone to older men – a smart move after all!

Dr. Weeks Comment:    For years, many of us who practice corrective medicine have maintained the minority opinion that prescribing bio-identical testosterone is not dangerous for men at risk for prostate cancer. This article from the current issue of Clinical Geriatrics proves us correct.  (Hint: it is the estrogen-receptive cells in the stromal layer of the prostate that are the vulnerable part,  so keep levels of estrogen low in men if you want to lower risk of prostate cancer.)

Remember: the sex hormones (estrogen, progesterone, testosterone etc) all inter-convert and it is primarily estrogen that increases risk of cancer (prostate, breast, ovarian, cervical, endometrial, etc).  Furthermore, there are 3 main human estrogens:  E1,  E2 &  E3 and, generally speaking E1 is more carcinogenic, E2 less so and E3 is preventive against cancer.  All these hormones should be tested in your blood to determine your cancer risk. (Note that in my opinion, salivary tests for these hormones is inaccurate and not recommended. )

POINT: Testosterone Therapy in Older Men: The Next Big Thing in Medicine?

Source:  Clinical Geriatrics  July 2009  p 22

 

Authors:

Abraham Morgentaler, MD, FACS

Introduction

The Holy Grail for geriatric medicine would be a treatment or medication that allowed older individuals to feel younger and more robust, and that increased longevity. In the past, any treatment that purported to demonstrate such effects has been equated with snake oil. Yet, it is fair to say that there has been a reasonable expectation that medical science would one day find such a treatment, usually based on studies that will help delineate the biochemical basis of aging, and hence provide insight into avenues of modifying or reversing this biochemical process. Surprisingly, accumulating evidence indicates that an old treatment may already provide many of the benefits one associates with youthfulness and health: testosterone therapy for testosterone-deficient men.

Clinicians tend to have an immediate resistance to considering this possibility. Just the word “testosterone” brings to mind unsavory associations, such as cheating athletes, body building use of steroids, and endless Internet spam, or advertisements promoting incredible virility-enhancing supplements via stimulation of “natural” testosterone-like supplements. Anti-aging enthusiasts have in some cases asserted that testosterone is a solution to a variety of problems for which evidence is lacking. Apart from these affronts to the properly skeptical medical scientist, worrisome reports regarding testosterone therapy have appeared in the literature over several decades, including the potential for stimulating dormant prostate cancer, liver toxicity, hypertension, heart disease, and lipid abnormalities. Additional hurdles inhibiting the use of testosterone therapy include the perception that testosterone therapy is primarily indicated for sexual pleasure, as well as the viewpoint that testosterone deficiency represents a normal aging process that does not merit treatment.

Testosterone therapy thus suffers from the soft prejudice of familiarity. Yet, recent scientific information indicates that the treatment of testosterone deficiency may provide some of the most far-reaching benefits currently available for aging men in terms of overall health and metabolic changes, with a favorable side-effect profile, including reassuring new evidence regarding prostate cancer. It is time for clinicians to suspend old prejudices in order to more objectively evaluate testosterone therapy for their older male patients.

Case Vignette

SD was a 67-year-old man who was seen with his wife of 30 years for absent libido, fatigue, lack of energy, and frequent naps. “He’s never been like this,” reported his wife. “He was always someone who had a lot of energy.” The patient denied depression. His past medical history was notable for prostate cancer treated with radical prostatectomy 5 years previously, followed by external beam radiation therapy for biochemical recurrence. Despite having a penile prosthesis for prior treatment of erectile dysfunction, he and his wife no longer engaged in sexual activity due to SD’s lack of libido. Blood tests revealed undetectable prostate-specific antigen (PSA) and markedly reduced total and free testosterone. A DXA scan was normal. Body composition showed 39% body fat.

After discussion of risks, the patient began treatment with testosterone gel. At 6 months, libido had returned, and SD and his wife had resumed regular intercourse. He felt more energetic, and his wife reported that he no longer took naps. Body fat declined to 36%, lean mass increased by 1.5 kg, and fat mass declined by 2.0 kg. PSA remained undetectable.

Multiple Benefits of Testosterone Therapy

As this case demonstrates, testosterone therapy may have a wide range of benefits for men, including improvement in sexual and nonsexual symptoms, as well as metabolic changes that promote health.1,2 The loss of fat and the gain in muscle routinely seen with testosterone therapy1,2 represents a nontrivial change in body composition that has implications for cardiovascular and metabolic health. In addition, this case underscores the changing attitudes regarding testosterone therapy and prostate cancer.3 Whereas only a few years ago it was feared that testosterone therapy might convert occult prostate cancer into clinical disease, new evidence that serum testosterone appears unrelated to prostate cancer risk4 has shifted the dialogue so that even men with a prior history of prostate cancer are now considered by some clinicians to be candidates for testosterone therapy under certain circumstances.5

Diabetes and Cardiovascular Health

Although the field still awaits a large-scale, long-term controlled study of testosterone therapy, there are a substantial number of observational and interventional studies that strongly indicate important links between testosterone and diabetes, and testosterone and cardiovascular health. Not only is the prevalence of low testosterone approximately 30-50% in ambulatory men with diabetes,6 but testosterone therapy has been shown to reduce insulin resistance.7 In longitudinal studies, men in the lowest quartile for testosterone values demonstrated more than double the risk of subsequently developing diabetes and the metabolic syndrome.8,9 In the Rotterdam study, men with the lowest third of testosterone values had five times the prevalence of significant aortic atherosclerosis as compared to men with higher testosterone values.10 In addition, testosterone-deficient men with known exercise-induced angina were able to exercise longer when treated with testosterone than men treated with placebo.11 Finally, cardiovascular health has been shown to be related to serum testosterone concentrations, with men with low testosterone demonstrating an increase in cardiovascular mortality.12

Other Benefits

Osteoporosis affects approximately 6% of men, and one of the best known risk factors is testosterone deficiency.13 Testosterone therapy produces significant improvement in bone density,2,14 with progressive improvement for as long as 3 years. In a recent study, men in the lowest quartile of testosterone values demonstrated an increased risk of low-trauma fractures.15

Most provocatively, there are now several longitudinal studies that have shown that men with low testosterone have reduced longevity as compared to men with higher testosterone, even when adjusted for other comorbidities.16,17 Of course, these observational studies are insufficient to conclude that normalization of serum testosterone will translate into greater longevity, yet there is now a basis for understanding why low testosterone may predispose to greater mortality, due to the impact of testosterone on cardiovascular and metabolic health parameters.

What Are the Risks?

It is important to emphasize to patients that the goal of testosterone therapy is to restore normal circulating levels of a naturally existing hormone,1 as with thyroid deficiency. This treatment is distinct from the use of supraphysiologic doses of testosterone in otherwise healthy individuals for body building or performance enhancement, a practice that should be condemned.

As noted above, the common concern that testosterone therapy may result in more rapid growth of prostate cancer has been shown to lack scientific support.3 It appears that the growth requirement of prostate cancer for androgens is satisfied at quite low serum testosterone concentrations,18 explaining why men with high endogenous testosterone are at no greater risk of cancer development or recurrence than men with low endogenous testosterone concentrations.4 Biochemically, it has been shown that the androgen receptor becomes maximally bound with androgen at androgen concentrations of 60-90 ng/dL.19

Many of the historical concerns regarding testosterone therapy have been abandoned. Current treatment formulations at physiologic doses (injections, gels, patches, implants) do not have any hepatic or renal toxicity, and do not negatively alter the lipid profile.20 Hepatotoxicity is limited to older oral forms of testosterone therapy; their use is thus strongly discouraged.20

The risks of testosterone therapy include erythrocytosis in approximately 4-5%, occasional cases of acne, and rare development of gynecomastia or testicular atrophy. Sperm production is greatly reduced during testosterone therapy, which means that testosterone therapy is contraindicated in men who are actively pursuing pregnancy with their partner.20

Treatment

The goal of treatment is to restore serum testosterone levels to normal. Whereas there is considerable debate as to what is “normal,” clinical experience suggests that optimal benefits are seen when testosterone levels are raised into the upper third of the normal range (eg, 600-800 ng/dL). However, lower levels may be adequate for symptom improvement in many men.

Choices of treatment include topical gels, patches, injections, implantable pellets, and a buccal tablet. Gels and patches require daily application, injections are given intramuscularly every 1-3 weeks, and pellets may provide adequate serum testosterone concentrations for 3-5 months. Serum monitoring is mandatory for transdermal modalities since absorption is not uniform and dosage may need to be adjusted to reach therapeutic levels.

Additional Considerations

A special concern among clinicians who see older individuals is to avoid over-medicalizing normal aspects of aging. My own perspective on this issue is that we already treat a great many medical conditions associated with aging, including impairments in vision, hearing, joints, and cardiac function. Even cancer is age-related. We treat all of these to improve quality of life, or to extend life. Since testosterone therapy may provide valuable symptomatic and health benefits to many men, I do not see how this differs from other treatments we offer every day to our older patients. On the contrary, it is my opinion that it is discriminatory to deny a possibly beneficial treatment only because the condition is common in older men.

Conclusions

It is time that the medical community re-evaluates the health benefits of testosterone therapy. Although there is still much to be learned, it is no longer acceptable to suggest that the benefits are uncertain or that these relate only to sexual function. There can no longer be any doubt that a deficiency of testosterone is a meaningful risk factor for serious medical conditions such as diabetes, atherosclerosis, metabolic syndrome, and osteoporosis.

Although one may reasonably argue that the absence of large, randomized, placebo-controlled intervention trials means that broad recommendations regarding use of testosterone therapy in geriatric populations is not yet warranted, a more pertinent question for the clinician is: What should be done with the individual patient seen for characteristic symptoms of testosterone deficiency, such as chronic fatigue, weakness, or diminished libido? If serum testosterone levels are consistent with a diagnosis of testosterone deficiency, does this not merit consideration of a trial of testosterone therapy? If a thyroid deficiency were noted in a man presenting with fatigue, would there be the same reluctance to treat?

The real benefit of treatment is to our patients. Of course, not all men with testosterone deficiency will respond to testosterone therapy. But medical science has now progressed to a point where it can be reasonably stated that normalization of serum testosterone in men who are testosterone-deficient is likely to improve symptoms of fatigue, sexual dysfunction, weakness, or decreased muscle mass, and may even improve mood, sense of well-being, motivation, and osteoporosis. As a physician, one of the best things to hear from a patient is that our treatment caused him to feel “normal again.” Sometimes we have to blink twice in order to see what has been right in front of our eyes the whole time.

The author has received speaker honoraria from Auxilium, Solvay, and Watson; is a consultant for Indevus and Slate; and has received research grants from Indevus.

Dr. Morgentaler is Associate Clinical Professor of Surgery (Urology) at Harvard Medical School, and is the founder and director of Men’s Health Boston (www.MensHealthBoston.com). He is the author of Testosterone for Life, The Male Body, and The Viagra Myth.

Issue Number:

Volume 17 – Issue 7 – July 2009

Start Page:

22

End Page:

24

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 [pubished correction appears in J Clin Endocrinol Metab 2006;91(7):2688]. J Clin Endocrinol Metab 2006;91(6):1995-2010. Published Online: May 23, 2006.

2. Wang C, Cunningham G, Dobs A, et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab 2004;89:2085-2098.

3. Morgentaler A. Testosterone and prostate cancer: An historical perspective on a modern myth. Eur Urology 2006;50:935-939. Published Online: July 27, 2006.

4. Endogenous Hormones Prostate Cancer Collaborative Group, Roddam AW, Allen NE, Appleby P, Key TJ. Endogenous sex hormones and prostate cancer: A collaborative analysis of 18 prospective studies. J Natl Cancer Inst 2008;100:170-183. Published Online: January 29, 2008.

5. Morgentaler A. Testosterone replacement therapy and prostate cancer. Urol Clin North Am 2007;34:555-563, vii.

6. 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.

7. Yialamas MA, Dwyer AA, Hanley E, et al. Acute sex steroid withdrawal reduces insulin sensitivity in healthy men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2007;92:4254-4259. Published Online: August 28, 2007.

8. 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;27:1036-1041.

9. Kupelian V, Hayes FJ, Link CL, et al. Inverse association of testosterone and the metabolic syndrome in men is consistent across race and ethnic groups. J Clin Endocrinol Metab 2008;93:3403-3410. Published Online: June 17, 2008.

10. Hak AE, Witteman JC, de Jong FH, et al. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: The Rotterdam Study. J Clin Endocrinol Metab 2002;87:3632-3639.

11. English KM, Steeds RP, Jones TH, et al. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: A randomized, double-blind, placebo-controlled study. Circulation 2000;102:1906-1911.

12. 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;116:2694-2701. Published Online: November 26, 2007.

13. Madeo B, Zirilli L, Caffagni G, et al. The osteoporotic male: Overlooked and undermanaged? Clin Interv Aging 2007;2:305-312.

14. Amory JK, Watts NB, Easley KA, et al. Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone. J Clin Endocrinol Metab 2004;89:503-510.

15. Meier C, Nguyen TV, Handelsman DJ, et al. Endogenous sex hormones and incident fracture risk in older men: The Dubbo Osteoporosis Epidemiology Study. Arch Intern Med 2008;168(1):47-54.

16. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008;93:68-75. Published Online: October 2, 2007.

17. Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch Intern Med 2006;14-28;166:1660-1665.

18. Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: The Saturation Model and the limits of androgen-dependent growth. Eur Urol 2009;55(2):310-321. Published Online: September 25, 2008.

19. Ho SM, Damassa D, Kwan PW, et al. Androgen receptor levels and androgen contents in the prostate lobes of intact and testosterone-treated Noble rats. J Androl 1985;6:279-290.

20. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004;350:482-492.

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Dr. Weeks Comment:    For years, many of us who practice corrective medicine have maintained the minority opinion that prescribing bio-identical testosterone is not dangerous for men at risk for prostate cancer. This article from the current issue of Clinical Geriatrics proves us correct.  (Hint: it is the estrogen-receptive cells in the stromal layer of the…
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