Androgen Replacement

[Michael Scally MD]

Heart attacks in men using testosterone
Testosterone replacement therapy and cardiovascular events
http://www.bmj.com/content/349/bmj.g7230

In February 2014, The BMJ published a personal view by Sidney Wolfe of Public Citizen—a US anti-pharmaceutical pressure group trying to obtain black box warnings for testosterone products.1 The article presented summaries from two recent papers that claimed increased cardiovascular risk with testosterone replacement therapy (TRT).2 3

In July 2014, the Food and Drug Administration published a detailed response to Public Citizen, explaining why it rejected every aspect of the case and concluding that the credible medical literature tended to support a reduction in mortality with TRT.4 The FDA reported the glaring errors in the two papers that hundreds of readers had identified. The first paper did find an increase in cardiovascular events with TRT, but the authors recently had to modify their data to explain why more than 1000 men were omitted because their event occurred before TRT, while also admitting that more than 100 women had been included in a male only study. The second study looked only at non-fatal events in the first three months after starting TRT. However, treatments such as testosterone that reduce mortality from cardiovascular events inevitably increase the rate of non-fatal events because more people survive.

A recent long term study of 6355 men aged over 69 years and more than 19 000 controls showed no increase in coronary events overall but a reduction in the cohort at greatest risk.5 The treated group also had low baseline testosterone and high rates of erectile dysfunction, both proven markers of cardiovascular risk.

In the name of medical integrity, having provided a platform for pressure groups with a private agenda, The BMJshould publish outcomes that are considered conclusions based on the highest levels of medical evidence.

 

[Michael Scally MD]

Heart attacks in men using testosterone
Author’s reply to Hackett
http://www.bmj.com/content/349/bmj.g7245

In a response to my column,1 Hackett criticises the study by Finkle et al, which investigated about 55 000 men prescribed testosterone, considerably more than any previously published study assessing the cardiovascular risk of testosterone products.2 It found a significantly increased rate of non-fatal myocardial infarction in the three months after initial testosterone prescription compared with the previous year.3

Hackett challenges the validity of using non-fatal myocardial infarction as the primary outcome because testosterone’s ability to reduce mortality from cardiovascular events would increase the rate of non-fatal events as more men would have survived. This is rebutted by a recent meta-analysis of 27 randomised testosterone trials, which identified 33 cardiovascular related deaths (22 testosterone arm and 11 placebo arm), for which the odds ratio was similar 1.42 (95% CI 0.70 to 2.89) to the estimate for all cardiovascular related events. In 14 trials not funded by the drug industry the risk of a cardiovascular related event on testosterone therapy was greater (2.06, 1.34 to 3.17) than in drug industry funded trials (0.89, 0.50 to 1.60).4

Hackett also mentioned the US Food and Drug Administration’s rejection of our petition for a black box warning about cardiovascular risks but disregarded the Canadian government’s contrasting action the same day: “Health Canada is advising patients and healthcare professionals of new safety information regarding testosterone hormone replacement products and a risk of serious and possibly life-threatening cardiovascular (heart and blood vessel) problems . . . Health Canada has recently completed a safety review on testosterone replacement products. This review found a growing body of evidence (from published scientific literature and case reports received by Health Canada and foreign regulators) for serious and possible life-threatening heart and blood vessel problems such as heart attack, stroke, blood clot in the lungs or legs; and increased or irregular heart rate with the use of testosterone replacement products.”5

Perhaps this makes Health Canada, as Hackett characterises us, an “anti-pharmaceutical pressure group.” Thus far, neither the FDA nor the European Medicines Agency has acknowledged the serious cardiovascular risk of testosterone products.

 

[Michael Scally MD]

Storrs C. The Other T Party. Scientific American. 2014;311:32-4. http://www.nature.com/scientificamerican/journal/v311/n4/full/scientificamerican1014-32.html

Doctors around the world have written a surprising number of prescriptions for testosterone treatment in recent years. Nearly 3 percent of American men aged 40 and older are thought to have received such scripts in 2011—three times the percentage in 2001. (If confirmed, the 2011 ratio could mean that perhaps two million older men in the U.S. have been given prescriptions for testosterone.) Originally intended for men who have difficulty producing sex hormones because of damage or disease in their testes or other parts of the endocrine system, testosterone replacement therapy has become increasingly popular with middle-aged and older men who do not have clear deficits but who nonetheless hope to lessen some of the symptoms of aging, including fatigue, muscle wasting and lack of sex drive.

In truth, no one knows whether the hormone can offer any of the health benefits that its proponents claim for aging males. Well-designed, placebo-controlled trials of the drug in men who do not meet the standard criteria for treatment have been scant in number, and their results have been inconsistent.

As testosterone therapy becomes more widespread, a growing number of medical experts worry that it has become too easy for men to get the hormone—whether from their own physicians or stand-alone “low T” clinics—and that many users could be putting themselves at risk for worse conditions than those they are trying to counteract.

Easy Access

Testosterone, as produced by the body, is a versatile hormone. In addition to maintaining sperm production, the molecule helps many tissues to grow: it increases muscle and bone mass, as well as the production of red blood cells—all of which are vital for energy and strength. Disease or injury in the testes or pituitary gland—a part of the brain that instructs the testes to produce testosterone—can hinder the body's ability to make the hormone. When testosterone levels dip too low, men can become depressed and lethargic, lose interest in sex, and lose some of their muscle and body hair.

While the potential risks associated with taking supplemental testosterone—particularly in otherwise healthy men—are not well studied, concern has focused on whether extra amounts of the hormone might damage the prostate, heart or brain. Many prostate tumors depend on testosterone to grow, so increasing the level found in the blood might nudge normal cells to become malignant or push malignant cells to become more aggressive. In addition, two recent studies found an increase in heart attacks and strokes among older men taking testosterone—which the authors speculated might occur if the drug increased clotting risk and drove up blood pressure. Earlier this year the U.S. Food and Drug Administration announced that it is studying the matter to see whether stronger regulations are needed. In the meantime, the agency now requires all testosterone products to contain a warning label about the potential for blood clots.

As long as testosterone therapy was available only by injection, its use was largely limited to individuals with testicular injuries or other severe ailments. The treatment markedly improves mood and libido in men with these conditions, and the FDAapproved the drug for those situations. But fear of needles no doubt kept some men from seeking treatment.

Individuals were more willing to consider their options once pharmaceutical companies figured out how to deliver the drug more easily. A transdermal patch that delivered the medicine through the skin of the scrotum became available in 1993. (Subsequent patches could be applied to the arms, back and thighs.) But the number of men taking supplemental testosterone really began to soar in 2000, with the introduction of an even easier-to-use gel that could be rubbed on the shoulders, thighs or armpits.

Greater ease of use also led to an expansion in the number of conditions for which doctors considered testosterone therapy to be a plausible treatment in spite of any supportive data. Perhaps an extra dose of testosterone could be helpful for otherwise healthy men whose hormone levels had faded with age or because they were obese or suffered from diabetes? (It is unclear precisely why testosterone levels decline for certain individuals in these situations.) In addition, some men who did not have testicular injuries desired the sex hormone because they thought it would treat erectile dysfunction or boost their mood.

Blind Guides

Given the continuing uncertainty about the hormone, the Endocrine Society, an international organization of health care professionals focused on hormone research and endocrinology, advises doctors to perform two blood tests to confirm below-typical levels of testosterone and rule out other potential causes of their patients' symptoms before writing a prescription. Yet the most recent research suggests that between 25 and 40 percent of patients receiving testosterone replacement therapy never had a blood test to measure their testosterone before starting treatment.

Preliminary findings by Jacques Baillargeon, director of the epidemiology division in the department of preventive medicine and community health at the University of Texas Medical Branch at Galveston, and his colleagues offer clues as to why so many men get testosterone prescriptions without the recommended blood work. According to their analyses of insurance claims databases, about 70 percent of men who have tried testosterone therapy did so after seeing a primary care physician, not a urologist or endocrinologist. Although Baillargeon will not speculate about why primary care physicians are more likely to write a prescription without first ordering a blood test, Glenn Cunningham, a professor of medicine and an endocrinologist at the Baylor College of Medicine, suggests that perhaps the generalists are less familiar with the Endocrine Society's guidelines.

Other sources of testosterone include increasingly common low T clinics, many of which require men to pay for prescriptions out of pocket, prompting Baillargeon to suspect “potentially inappropriate prescribing practices.”

The clinics say their staff are trained in hormone medicine and do the appropriate blood work, but such claims are hard to verify without a data trail from insurance filings. In addition, the clinics are not reviewed or regulated by medical organizations or government groups.

New Limits?

The troubling spread of testosterone therapy in men has parallels to the early use of hormone replacement therapy in postmenopausal women. Starting in the 1990s, a series of studies suggested that many women who took a combination of estrogen and progestin as they grew older would suffer less from heart disease. But by 2004, after researchers had completed two major parts of the Women's Health Initiative—which together formed a massive study of 27,347 women that compared treatment with a placebo in a scientifically rigorous way—doctors realized hormone therapy does more harm than good in most women over the long term.

The study initially prompted a dramatic drop in the number of women taking prescription hormones. Since then, however, a more nuanced view has come into focus: the proved benefit of relieving menopausal symptoms such as hot flashes is worth the risk for some women, provided they limit treatment to the first several years after menopause. “I think we are less naive” than before the Women's Health Initiative, says Bradley Anawalt, a University of Washington professor of medicine and chair of the Endocrine Society's Hormone Health Network. “We are recognizing there is never a simple answer, and we have to discover who benefits and who gets harmed.”

For testosterone, some of those answers may soon be forthcoming. Results from a series of scientific studies detailing exactly who might gain from testosterone therapy, and under what circumstances, are expected to be published starting later this year. The series started in 2009, when the U.S. government funded a team of researchers to recruit and study participants for the Testosterone Trial—a group of seven long-term studies of how testosterone therapy affects sexual activity, energy level, memory, heart and bone health, and the ability to walk a certain distance. The trial followed 788 men, aged 65 and older, whose testosterone levels in the blood were much lower than average. Half the men (the experimental group) applied a gel with testosterone to their shoulders, abdomen or upper arms each day for a year, and the other half (the control group) used a gel containing a placebo. Researchers also monitored prostate cancer risk, based on prostate-specific antigen levels and a rectal exam, and stroke risk, based on red blood cell levels during the treatment year and for at least a year afterward.

Studies of the risks of testosterone use would likely follow only if the data on benefits were promising. Health researchers often look first at benefits of a treatment because theses studies call for fewer test subjects than risk studies do. Even though such randomized placebo-controlled trials can take years to conduct, they offer the best hope for separating truth from wishful thinking.

 

[Michael Scally MD]

Testosterone Replacement Therapy Faces FDA Scrutiny

The emergence of TRT as a multibillion-dollar industry without appropriate supporting data or oversight of its proper usage emphasizes the need for stricter controls as well as reassessment of approval pathways when the usage is not consistent with approved labeling.

However, this advisory committee meeting represented a remarkable convergence of many disciplines—academics, industry, regulatory scientists, expert panel, and the public—that collaboratively and effectively charted a blueprint for better controls, further study, and educational outreach to both physicians and patients for this important class of drugs.

The safety of the public was well served by this process.

Garnick MB. Testosterone Replacement Therapy Faces FDA Scrutiny. JAMA.Published online December 11, 2014. http://jama.jamanetwork.com/article.aspx?articleid=2042936

 

[Michael Scally MD]

Bosland MC. Testosterone Treatment is a Potent Tumor Promoter for the Rat Prostate. Endocrinology:en.2014-1688. http://press.endocrine.org/doi/abs/10.1210/en.2014-1688

Response to RE: Testosterone Treatment is a Potent Tumor Promoter

Bosland MC. Author's Response to RE: Testosterone Treatment is a Potent Tumor Promoter for the Rat Prostate. Endocrinology 2014;1(1):L3-L4. http://press.endocrine.org/doi/full/10.1210/en.2014-1911

I am very concerned by the final statement in the comments by Dr Traish, Dr Morgentaler, and Dr Khera about my report on the carcinogenic and tumor promoting effects of testosterone treatment in male rats that “comments on T therapy based on results from rodents do not belong in this report” (1).

Results from studies in rodents are used by the Food and Drug Administration and Environmental Protection Agency, as well as by their European counterparts and international organizations, such as the International Agency for Research on Cancer (World Health Organization), to evaluate the carcinogenic risk to humans of exposures to drugs and other chemicals.

A statistically significant increase in the occurrence of malignant tumors in such studies is considered an indication that the drug or chemical tested may be carcinogenic to humans. Typically, drugs in development for medical use that test positive in such studies are not pursued further, and other chemicals that cause malignancies in rodent experiments are regulated on the basis of the study results.

Testosterone treatment significantly increased the number of animals with malignant tumors and caused prostate carcinomas in my study and others, quoted in my article, have also found such a prostate tumor response. Prostate tumors are extremely rare in untreated aged Wistar rats, including the Cpb:WU strain used in my study, and finding rare malignancies in rodents exposed to chemicals is commonly considered a strong indication that the compound tested is a rodent carcinogen.

After a single carcinogen exposure to cause DNA damage and mutations in the prostate, long-term testosterone treatment caused a massive prostate cancer response in my study, even at a dose that did not significantly elevate circulating testosterone. This tumor response of WU rats to N-methyl-N-nitrosourea plus testosterone treatment has been remarkably stable for over 25 years, indicating that “genetic drift” is not a problem.

These findings, taken together, are thus clear reason to be concerned about the risk of prostate cancer in testosterone-treated men, and they form the basis for the last sentence in my report, which disturbed Dr Traish, Dr Morgentaler, and Dr Khera, who left out the beginning of that sentence: “Until adequate human studies are available.”

The assertion that the findings in rats are contradicted by a large body of evidence in humans is incorrect. Of the 6 publications mentioned in the letter, 1 does not deal with prostate cancer (2) and 1 is a review article by Dr Khera and Dr Morgentaler (3).

Of the 4 remaining publications, 1 deals with short-term follow up of men treated with testosterone and compares their low occurrence of prostate cancer with the incidences found in 2 large-scale screening studies of men presumably not treated with testosterone (4); this approach is not very convincing.

Another reference (5) is a metaanalysis of 9 small studies, but the numbers of subjects and cancer cases in these are too low to be meaningful. The 2 other references (6, 7) report on the lack of an association between prediagnostic testosterone serum levels and subsequent risk of prostate cancer (see also Ref. 8); such studies suffer from several limitations and cannot be directly compared with findings in untreated rats because of the large difference in “spontaneous” prostate cancer between rats and humans.

Of note, my study entailed long-term testosterone exposure and is thus relevant to potential risks in humans of long-term testosterone treatment. The statement in the letter that “multiple reports indicate an association between low levels and increased risk” is not supported by references and appears to be based only on studies from their group (3).

The development of endocrine tumors in WU rats is quite comparable with aging humans who also develop microscopic size tumors of the pituitary and thyroid glands and adrenal cortex with significant frequency (9–12).

Of note, in my study, there was no association apparent between the induction of prostate carcinomas and the development of tumors in endocrine organs or other tissues. As mentioned in the letter, at higher doses of testosterone, the prostate cancer response seemed to diminish somewhat, which is interesting and worth commenting on.

Most, perhaps all, steroid hormones act on their receptors in a biphasic manner, and dihydrotestosterone is no exception (13). Thus, the reduced tumor response at higher testosterone doses would provide additional support for the notion that androgen receptor mediation is involved.

The observation that the androgen precursor dehydroepiandrosterone (DHEA) reproducibly inhibited prostate cancer induction in this rat model (14) is interesting and puzzling. DHEA may have a mode of action that does not involve androgen production, because a fluorinated DHEA analog that cannot be converted to androgen also inhibited prostate carcinogenesis in this model (15).

In closing, there is no large body of evidence or extensive human data indicating a lack of risk of prostate cancer with testosterone treatment of aging men and the conclusions in my report that adequate “retrospective and prospective epidemiology studies …. are urgently needed” and until such studies are available, “it appears prudent … to avoid testosterone use by men for nonmedical purposes” are in my personal and professional opinion justified.

References

1. Traish AM, Morgentaler A, Khera M. Re: testosterone treatment is a potent tumor promoter for the rat prostate. Endocrinology. 2015;156:L1.

2. Cui Y, Zhang Y. The effect of androgen-replacement therapy on prostate growth: a systematic review and meta-analysis. Eur Urol. 2013;64:811–822.

3. Khera M, Crawford D, Morales A, Salonia A, Morgentaler A. A new era of testosterone and prostate cancer: from physiology to clinical implications. Eur Urol. 2014;65:115–123.

4. Haider A, Zitzmann M, Doros G, Isbarn H, Hammerer P, Yassin A. Incidence of prostate cancer in hypogonadal men receiving testosterone therapy: observations from five year-median follow-up of three registries. J Urol. [published ahead of print June 26, 2014]. doi: 10.1016/j.juro.2014.06.071

5. Cui Y, Zong H, Yan H, Zhang Y. The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2014;17:132–143.

6. Endogenous Hormones and 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.

7. Muller RL, Gerber L, Moreira DM, Andriole G, Castro-Santamaria R, Freedland SJ. Serum testosterone and dihydrotestosterone and prostate cancer risk in the placebo arm of the reduction by dutasteride of prostate cancer events trial. Eur Urol. 2012;62:757–764.

 

[Michael Scally MD]

RE: Testosterone Treatment Is a Potent Tumor Promoter for the Rat Prostate

Traish AM, Morgentaler A, Khera M. RE: Testosterone Treatment Is a Potent Tumor Promoter for the Rat Prostate. Endocrinology 2014;1(1):L1-L2. http://press.endocrine.org/doi/full/10.1210/en.2014-1843

We are disturbed by Dr Bosland's provocative comment that testosterone (T) is a carcinogen causing prostate cancer (PCa) (1), because this assertion is contradicted by a large body of evidence in humans (2–7) and is unsupported by his own experimental results (1).

Dr Bosland bases his conclusion on experiments in a rodent model susceptible to developing cancer in endocrine and nonendocrine organs (8–10). In this study (1), animals were treated daily for 21 days with cyproterone acetate, followed by T propionate followed by nitroso-methylurea, a known carcinogen, and then followed by T implantation (1).

Dr Bosland ignored 2 key observations from his own experiments:
1) untreated animals failed to develop prostate tumors (see table 2 in Ref. 1) despite physiological circulating T (1), and
2) a strong PCa response was seen in animals with the lowest T but not the highest T doses.

Clearly, physiological T levels alone are not carcinogenic in this model or in humans, where large prospective longitudinal studies have demonstrated no increased PCa risk among men with higher serum T compared with men with lower T (2).

Within this experimental model, it is interesting that dehydroepiandrosterone, a T precursor, has been shown to delay tumor induction by nitroso-methylurea (9).

There can be no reasonable extrapolation to humans from results in an animal model that is prone to genetic drift and spontaneous tumor development (8–10), treated with a known carcinogen, especially in light of evidence from human studies that do not support the premise that T is a carcinogen in human prostate (2–7).

Although there may be valuable insights into the mechanisms of oncogenesis derived from these experiments (1), we reject any and all conclusions regarding human implications based on artificial and unusual model, particularly when they are contradicted by extensive human data (2–7).

Indeed, in humans, there are no compelling data indicating that high T levels are associated with greater PCa risk or aggressiveness. On the contrary, multiple reports indicate an association between low levels and increased risk. Further, it is well known that intraprostatic T concentrations are highest in normal prostates of young men, yet the incidence of PCa in young men is small.

We are greatly disturbed by Dr Bosland's comment: “… it appears prudent to limit 'testosterone therapy' to those men who suffer from symptomatic clinical hypogonadism, to consider the lowered circulating testosterone levels occurring in aging men a physiological phenomenon and not a disease that requires treatment, and to avoid testosterone use by men for nonmedical purposes” (1).

Although we agree that T therapy should be restricted to men with clinical hypogonadism, it should be clear that Dr Bosland's comments regarding age-related reductions in serum T, and their clinical impact represent his own personal opinions that are unsupported by evidence. Thus, comments on T therapy based on results from rodents do not belong in this report (1).

References

1. Bosland MC. Testosterone treatment is a potent tumor promoter for the rat prostate. Endocrinology. 2014;155:4629–4633.

2. Endogenous Hormones and 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.

3. Khera M, Crawford D, Morales A, Salonia A, Morgentaler A. A new era of testosterone and prostate cancer: from physiology to clinical implications. Eur Urol. 2014;65:115–123.

4. Haider A, Zitzmann M, Doros G, Isbarn H, Hammerer P, Yassin A. Incidence of prostate cancer in hypogonadal men receiving testosterone therapy: observations from five year-median follow-up of three registries. J Urol. [published ahead of print June 26, 2014].

5. Muller RL, Gerber L, Moreira DM, Andriole G, Castro-Santamaria R, Freedland SJ. Serum testosterone and dihydrotestosterone and prostate cancer risk in the placebo arm of the Reduction by Dutasteride of Prostate Cancer Events trial. Eur Urol. 2012;62:757–764.

6. Cui Y, Zong H, Yan H, Zhang Y. The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2014;17:132–143.

7. Cui Y, Zhang Y. The effect of androgen-replacement therapy on prostate growth: a systematic review and meta-analysis. Eur Urol. 2013;64:811–822.

8. Poteracki J, Walsh KM. Spontaneous neoplasms in control Wistar rats: a comparison of reviews. Toxicol Sci. 1998;45:1–8.

9. Rao KV, Johnson WD, Bosland MC, et al. Chemoprevention of rat prostate carcinogenesis by early and delayed administration of dehydroepiandrosterone. Cancer Res. 1999;59:3084–3089.

10. McCormick DL, Rao KV, Dooley L, et al. Influence of N-methyl-N-nitrosourea, testosterone, and N-(4-hydroxyphenyl)-all-trans-retinamide on prostate cancer induction in Wistar-Unilever rats. Cancer Res. 1998;58:3282–3288.

 

[DTdr2]

The New Testosterone Treatment: How You and Your Doctor Can Fight Breast Cancer, Prostate Cancer, and Alzheimer's
[ame="[url]http://www.amazon.com/The-New-Testosterone-Treatment-Alzheimers/dp/1616147237[/url]"]The New Testosterone Treatment: How You and Your Doctor Can Fight Breast Cancer, Prostate Cancer, and Alzheimer's: Edward Friedman, William Cane, Dr. Paul Savage: 9781616147235: Amazon.com: Books[/ame]

Thank you Scally for this recommendation. I'm just now getting around to reading it, and can't put it down. Very eye opening [emoji106]

 

[Michael Scally MD]

Pan M, Ramasamy R, Kovac JR. Is semen analysis necessary prior to the commencement of testosterone supplementation therapy in men of reproductive age? Can Urol Assoc J 2014;8(11-12):446-7. http://journals.sfu.ca/cuaj/index.php/journal/article/view/2259

A semen analysis (SA) should be performed on all men of reproductive age prior to the commencement of testosterone supplementation therapy (TST). A baseline SA has numerous benefits including the ability to unmask occult azoospermia, act as a baseline measure of reproductive function, and provide a recovery target for management of TST-induced testicular dysfunction. Physicians treating men of reproductive age with TST should incorporate SA as part of their initial treatment protocol.

 

[Michael Scally MD]

Zhao J, Schooling CM. Does falling testosterone with age among men underlie the increase in ischaemic heart disease. J Epidemiol Community Health. http://jech.bmj.com/content/early/2015/01/06/jech-2014-204483.short

BACKGROUND: Observationally, testosterone falls with age among men and ischaemic heart disease (IHD) increases with age, so testosterone is commonly assumed to protect against IHD. Here we examined whether IHD mortality rates among men increased faster with age in the USA than China, where testosterone in men remains stable throughout adulthood, and also whether the increase with age in mortality rates for IHD is faster than for other causes of death.

METHODS: Age-specific mortality rates from all causes, IHD, pneumonia and prostate cancer for men in the USA and China from 1991 to 1995 were obtained from the WHO, and considered in age groups because of non-linearity.

RESULTS: The risk of death from IHD in US men increased with age at the same rate as the risk of death from any cause. In China, the risk of death from IHD increased with age faster than the risk of death from any cause.

CONCLUSION: The data are not consistent with the assumption that a fall in testosterone with age causes IHD.

 

[Michael Scally MD]

Kim C, Cushman M, Kleindorfer D, Safford MM, Redberg RF, Lisabeth L. A Review of the Relationships between Endogenous Sex Steroids and Incident Ischemic Stroke and Coronary Heart Disease Events. Curr Cardiol Rev. http://benthamscience.com/journal/abstracts.php?journalID=ccr&articleID=127468

For decades, it has been recognized that men have a higher age-adjusted risk of ischemic cardiovascular (CVD) events compared to women, thus generating hypotheses that sex steroids contribute to CVD risk.

Potential mechanisms include genomic and non-genomic effects of sex steroids as well as mediation through classic CVD risk factors and obesity.

However, results from randomized studies suggest that sex steroid supplementation in men and women do not result in improved CVD outcomes and may increase CVD risk.

In contrast, prospective observations from endogenous sex steroid studies, i.e. among participants not using sex steroids, have suggested the opposite relationship.

We reviewed the findings of prospective observational studies in men (17 studies) and women (8 studies) that examined endogenous sex steroids and CVD risk.

These studies suggested a lack of association or that lower levels of testosterone or dihydrotestosterone are associated with higher CVD risk in both men and women.

Higher, rather than lower, estradiol levels were associated with higher CVD risk in women.

There were several significant gaps in the literature.
· First, it is unclear whether more sensitive measures of sex steroid levels might detect significant differences.
· Second, there are few prospective studies in women. Similarly, no studies report outcomes for high-risk groups such as African-Americans and Hispanics.
· Finally, few studies report upon ischemic coronary disease as opposed to ischemic stroke separately, although relationships between sex steroids and CVD may vary by vascular bed.

Future investigations need to examine high risk groups and to distinguish between subtypes of CVD.

 

[Michael Scally MD]

Klotz L. Testosterone therapy and prostate cancer-safety concerns are well founded. Nat Rev Urol 2015;12(1):48-54. http://www.nature.com/nrurol/journal/v12/n1/abs/nrurol.2014.338.html

Testosterone is a potent hormone with a variety of physiological effects. The diagnosis of androgen deficiency has increased dramatically over the past decade, along with the widespread use of testosterone supplementation therapy (TST).

The long-term effects of TST are uncertain, and the risk of overdiagnosis and overtreatment of men who have a normal age-related decline in testosterone is substantial.

The biology of the androgen receptor (AR) pathway is complex, and the saturation model does not take the heterogeneity of human prostate cancer into account.

Large-scale trials to confirm the safety of testosterone with respect to the risks of prostate cancer and cardiovascular disease with reasonable confidence limits have not been done, and existing data are insufficient to exclude these adverse events.

Instead, evidence suggests that prostate cancer could, in fact, be stimulated by TST, and that the risk of cardiovascular events is increased.

Overall, TST seems to impose significant risks, and should be used with caution.

 

[vgc]

I'd love to see some larger scale interventions with guys in their 30s. Lots of great information in this thread!

 

[Michael Scally MD]

Srinath R, Hill Golden S, Carson KA, Dobs A. Endogenous Testosterone and its relationship to preclinical and clinical measures of cardiovascular disease in the Atherosclerosis Risk in Communities (ARIC) Study. The Journal of Clinical Endocrinology & Metabolism. http://press.endocrine.org/doi/abs/10.1210/jc.2014-3934

Context: Epidemiologic studies suggest that endogenous testosterone (T) levels in males may be implicated in cardiovascular disease (CVD), however further clarification is needed.

Objective: We assessed the cross-sectional relationship between endogenous plasma T and mean carotid intima media thickness (cIMT), and the longitudinal relationship with incident clinical CVD events, cardiac mortality, and all-cause mortality using male participants in the Atherosclerosis Risk in Communities (ARIC) study.

Design: This study involved a subset of men from visit 4 of the ARIC study.

Setting: Community based cohort.

Participants: Males who provided a morning blood sample excluding those taking androgen therapy, with prevalent coronary heart disease (CHD), stroke, or heart failure (HF) (n=1558).

Intervention: None

Main Outcome Measures: Plasma T by liquid chromatography mass spectrometry and carotid IMT using high resolution B-mode ultrasound were obtained at visit 4. Incident CHD, HF, cardiac mortality and all-cause mortality were identified by surveillance through 2010 (median 12.8 years).

Results: Lower T was significantly associated with higher body mass index, greater waist circumference, diabetes, hypertension, lower HDL, and never smoking(p=0.01). T was not associated with mean cIMT in unadjusted or adjusted analyses.

Following multivariable adjustment, there was no association of quartile (Q) of T with incident CHD [hazard ratio (HR)=0.87(95%CI=0.60–1.26) for Q1; 0.97(95%CI=0.69–1.38) for Q2; 0.97(95%CI=0.69–1.36) for Q3 compared to reference of Q4] or for incident HF [HR=0.77(95%CI=0.46–1.29) for Q1; 0.72(95%CI=0.43–1.21) for Q2; 0.87(95%CI=0.53–1.42) for Q3 compared to reference of Q4]. Similarly there was no association of Q of T with mortality or cardiac-associated mortality.

Conclusions: Low male plasma T is cross-sectionally associated with key CVD risk factors, but after adjustment there was no association with mean cIMT, incident cardiac events, or mortality. Our results are reassuring that neither high nor low T levels directly predict atherosclerosis, but are a marker for other cardiovascular risk factors.

 

[Michael Scally MD]

Etminan M, Skeldon SC, Goldenberg SL, Carleton B, Brophy JM. Testosterone Therapy and Risk of Myocardial Infarction: A Pharmacoepidemiologic Study. Pharmacotherapy. http://onlinelibrary.wiley.com/doi/10.1002/phar.1534/abstract

BACKGROUND: Recent studies have provided conflicting and controversial results about the risk of cardiovascular events, including myocardial infarction (MI), with testosterone replacement therapy (TRT). The potential adverse effects of different TRT formulations and duration of therapy on MI risk are unknown.

METHODS: We performed a case-control study within a cohort of 934,283 men aged 45-80 from the IMS LifeLink Health Plan Claims Database. For each case of MI, four controls were identified using density-based sampling. Rate ratios (RRs) were computed for current and past TRT users. As a sensitivity analysis, the risk of MI before and after the start of a first-time TRT prescription in the same patient was also computed.

RESULTS: We identified 30,066 MI cases and 120,264 corresponding controls. Current use of TRT was not associated with an increased risk of MI (RR 1.01, 95% confidence interval [CI] 0.89-1.16); first-time users did show an increased risk (RR 1.41, 95% CI 1.06-1.87; number needed to harm 305). There was no association between MI and past TRT users and no differences among the different formulations. The RRs for current use and first-time use of TRT in men with a previous history of coronary artery disease were 1.05 (95% CI 0.79-1.41) and 1.78 (95% CI 0.93-3.40), respectively.

CONCLUSION: In this large observational study, an association between MI and past or current TRT use was not found. However, a statistically significant association was observed between first-time TRT exposure and MI, although the absolute risk was low.

 

[Michael Scally MD]

Lee WC, Kim MT, Ko KT, et al. Relationship between Serum Testosterone and Cardiovascular Disease Risk Determined Using the Framingham Risk Score in Male Patients with Sexual Dysfunction. World J Mens Health 2014;32(3):139-44. http://wjmh.org/DOIx.php?id=10.5534/wjmh.2014.32.3.139

PURPOSE: The aim of the present study aimed to evaluate the effect of testosterone on cardiovascular disease by using the Framingham Risk Score (FRS) in patients with sexual dysfunction.

MATERIALS AND METHODS: A total of 308 men with sexual dysfunction were enrolled in this study. Clinical assessments included the 15-item International Index of Erectile Function (IIEF), blood pressure measurement, and clinical laboratory indexes. The FRS, which predicts the incidence rate of cardiovascular diseases in the next 10 years, was calculated on the basis of age, gender, total cholesterol, smoking status, high density lipoprotein cholesterol, and systolic blood pressure.

RESULTS: The mean age of the 308 enrolled patients was 49.42+/-10.73 years, and the patients' mean body mass index (kg/m(2)) was 25.07+/-3.14. The mean total IIEF score was 28.44+/-18.06. The median total testosterone concentration was 3.2 ng/mL (interquartile range [IQR]: 2.3~3.2 ng/mL). The median calculated free and bioavailable testosterone concentrations were 0.052 ng/mL (IQR 0.039~0.070 ng/mL) and 1.30 ng/mL (IQR: 1.00~1.76 ng/mL), respectively.

The mean FRS was 10.47+/-6.45. The FRS tended to show a negative correlation with the total and calculated free testosterone levels, but this was not significant (p=0.064 and p=0.074, respectively). In the multiple linear regression analysis, a significant negative correlation was observed between the total testosterone level and the FRS (p=0.048).

CONCLUSIONS: The results suggest that the testosterone level is related to the FRS and that a high testosterone level may decrease the risk of cardiovascular disease.

 

[Michael Scally MD]

Pastuszak AW. Malignant medication? Testosterone and cancer. BJU Int 2015;115(2):179-80. http://onlinelibrary.wiley.com/doi/10.1111/bju.12822/full

Testosterone therapy (TTh) in men with hypogonadism is becoming more commonplace among urologists, endocrinologists and even primary practitioners. While the definition of hypogonadism remains a moving target, the literature reflects very clear benefits of TTh in appropriately selected patients.

As with any drug, the adverse effect profile helps to dictate the risk:benefit ratio and, over the past several years, numerous, primarily retrospective, analyses have provided mixed insights into the impact of TTh on cardiovascular disease and cancer, specifically prostate cancer.

Eisenberg et al. [1] take a step back from the focus on prostate cancer and evaluate the impact of TTh on general cancer incidence in a cohort of men treated in a single, large-volume andrology practice over 20 years.

The authors found no difference in either overall cancer incidence or in the prostate cancer incidence in men on TTh in comparison with men not on TTh. This finding is significant as it supports the hypothesis that testosterone does not harmfully affect either hormonally responsive (prostate cancer) or non-hormonally responsive malignancies. Interestingly, the authors also observe a lower rate of all cancers in men on testosterone therapy.

While not statistically significant, this finding is consistent with that of at least one other study focused on prostate cancer, in which men with high-risk prostate cancer receiving exogenous testosterone had a lower recurrence rate than a matched control group [2]. If borne out in future studies, a protective relationship between TTh and cancer would indeed reflect a novel benefit of treatment.

Nevertheless, at this time the jury remains out on a definitive assessment of the effects of TTh on both cancer as well as cardiovascular disease, and will probably continue to do so until controlled, prospective studies are completed.

Numerous, mostly retrospective studies have examined the effects of endogenous testosterone and of the administration of exogenous testosterone, primarily on prostate cancer. While the details of these studies are beyond the scope of the present editorial, their findings have varied with regard to whether testosterone does or does not have effects on cancer incidence, biopsy findings, grade, recurrence rates and margin status, preventing a clear perspective on the effects of testosterone on cancer.

Similarly, studies evaluating the impact of TTh on cardiovascular disease have also widely varied in their conclusions [3, 4]. Several recent large retrospective studies have found a detrimental relationship between TTh and cardiovascular disease in specific male populations, but have come under withering criticism from the community, with significant doubts cast regarding the veracity of their findings [5, 6].

The growing popularity of TTh has subjected it to a level of scrutiny applied to few other medications, resulting in a slew of peer-reviewed publications of varying quality and conclusions. In the effort to safeguard patients, investigators have hurriedly carried out retrospective data evaluation, which, by design, limits compensation for confounding factors and unfortunately results in an overall murky understanding of long-term adverse events related to TTh.

Nevertheless, the clinical benefits of TTh are clear, and many patients are satisfied with the results of treatment. While physicians should remain the stewards of patient care, informed consent and a patient's acceptance of both the known as well as the unknown risks of testosterone treatment should continue to be an integral part of the initiation and continuation of TTh, until additional high-quality data from clinical trials become available in the coming years.

References

1 Eisenberg ML, Li S, Betts P et al. Testosterone therapy and cancer risk. BJU Int 2015;115:317–321.

2 Pastuszak AW, Pearlman AM, Lai WS et al. Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy. J Urol 2013;190:639–644.

3 Basaria S, Coviello AD, Travison TG et al. Adverse events associated with testosterone administration. N Engl J Med 2010;363:109–122.

4 Shores MM, Smith NL, Forsberg CW et al. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 2012;97:2050–2058.

5 Vigen R, O'Donnell CI, Baron AE et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013;310:1829–1836.

6 Finkle WD, Greenland S, Ridgeway GK et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS ONE 2014;9:e85805.

 

[Michael Scally MD]

Kang Y, Li HJ. The Effect of Testosterone Replacement Therapy on Prostate-Specific Antigen (PSA) Levels in Men Being Treated for Hypogonadism: A Systematic Review and Meta-Analysis. Medicine (Baltimore) 2015;94(3):e410. http://journals.lww.com/md-journal/...f_Testosterone_Replacement_Therapy_on.14.aspx

Testosterone replacement therapy is used for the treatment of age-related male hypogonadism, and prostate-specific antigen (PSA) is a primary screening tool for prostate cancer. The systematic review and meta-analysis aimed to determine the effect of testosterone replacement therapy on PSA levels.Medline, Cochrane Library, EMBASE, and Google Scholar databases were searched until February 28, 2014, and inclusion criteria were as follows: randomized controlled trial; intervention group received testosterone/androgen replacement therapy; control group did not receive treatment; and no history of prostate cancer.

The primary outcome was change of PSA level between before and after treatment. Secondary outcomes were elevated PSA level after treatment, and the number of patients who developed prostate cancer.

After initially identifying 511 articles, 15 studies with a total of 739 patients that received testosterone replacement and 385 controls were included. The duration of treatment ranged from 3 to 12 months.

Patients treated with testosterone tended to have higher PSA levels, and thus a greater change than those that received control treatments (difference in means of PSA levels = 0.154, 95% confidence interval [CI] 0.069 to 0.238, P < 0.001). The difference in means of PSA levels were significant higher for patients that received testosterone intramuscularly (IM) than controls (difference in means of PSA levels = 0.271, 95% CI 0.117-0.425, P = 0.001). Elevated PSA levels after treatment were similar between patients that received treatment and controls (odds ratio [OR] = 1.02, 95% CI 0.48-2.20, P = 0.953).

Only 3 studies provided data with respect to the development of prostate cancer, and rates were similar between those that received treatment and controls.

Testosterone replacement therapy does not increase PSA levels in men being treated for hypogonadism, except when it is given IM and even the increase with IM administration is minimal.

 

[MR10X]

After PCa treatment which also involed ADT my PSA was .09,this was while my test level was still at castration levels. After a 3 month cycle of test E at 120 mg a week and level of 1580 3 days after injection and then getting off it my natural levels came back to 442 TT and 3.8 FT,PSA done then was .62. 6 months later with normal test levels at 493 TT and 4.7 FT my PSA came back .43.Getting another PSA done in April.....

 

[Michael Scally MD]

Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Testosterone Therapy and Cardiovascular Risk: Advances and Controversies. Mayo Clinic Proceedings. http://www.mayoclinicproceedings.org/article/S0025-6196(14)00925-2/abstract

Two recent studies raised new concerns regarding cardiovascular (CV) risks with testosterone (T) therapy. This article reviews those studies as well as the extensive literature on T and CV risks.

A MEDLINE search was performed for the years 1940 to August 2014 using the following key words: testosterone, androgens, human, male, cardiovascular, stroke, cerebrovascular accident, myocardial infarction, heart attack, death, and mortality. The weight and direction of evidence was evaluated and level of evidence (LOE) assigned.

Only 4 articles were identified that suggested increased CV risks with T prescriptions: 2 retrospective analyses with serious methodological limitations, 1 placebo-controlled trial with few major adverse cardiac events, and 1 meta-analysis that included questionable studies and events.

In contrast, several dozen studies have reported a beneficial effect of normal T levels on CV risks and mortality.

Mortality and incident coronary artery disease are inversely associated with serum T concentrations (LOE IIa), as is severity of coronary artery disease (LOE IIa). Testosterone therapy is associated with reduced obesity, fat mass, and waist circumference (LOE Ib) and also improves glycemic control (LOE IIa). Mortality was reduced with T therapy in 2 retrospective studies.

Several RCTs in men with coronary artery disease or heart failure reported improved function in men who received T compared with placebo. The largest meta-analysis to date revealed no increase in CV risks in men who received T and reduced CV risk among those with metabolic disease.

In summary, there is no convincing evidence of increased CV risks with T therapy.

On the contrary, there appears to be a strong beneficial relationship between normal T and CV health that has not yet been widely appreciated.

 

[Michael Scally MD]

Add a Black Box Warning About the Increased Risks of Heart Attacks and Other Cardiovascular Dangers to the Product Labels of all Testosterone-Containing Drugs Presently on the Market in the U.S.

Citizen Petition & FDA Response - http://www.noticeandcomment.com/FDA-2014-P-0258-fdt-35570.aspx