Myths and Truths of Growth Hormone and Testosterone Therapy in Heart Failure

Cam T Nguyen; Alistair Aaronson; Ryan P Morrissey; Megha Agarwal; Robert D Willix; Ernst R Schwarz

Abstract and Introduction

Abstract

Heart failure is a chronic clinical syndrome with very poor prognosis. Despite being on optimal medical therapy, many patients still experience debilitating symptoms and poor quality of life. In recent years, there has been a great interest in anabolic hormone replacement therapy – namely, growth hormone and testosterone – as an adjunctive therapy in patients with advanced heart failure. It has been observed that low levels of growth hormone and testosterone have been associated with increased mortality and morbidity in patients with heart failure. Animal studies and clinical trials have shown promising clinical improvement with hormonal supplementation. Growth hormone has been shown to increase ventricular wall mass, decrease wall stress, increase cardiac contractility, and reduce peripheral vascular resistance, all of which might help to enhance cardiac function, resulting in improvement in clinical symptoms. Likewise, testosterone has been shown to improve hemodynamic parameters via reduction in peripheral vascular resistance and increased coronary blood flow through vasodilation, thereby improving functional and symptomatic status. To date, growth hormone and testosterone therapy have shown some positive benefits, albeit with some concerns over adverse effects. However, large randomized controlled trials are still needed to assess the long-term safety and efficacy.

Introduction

Heart failure (HF) is a chronic, complex clinical syndrome of multiple etiologies that results in structural and functional changes whereby the heart needs higher-than-normal filling pressures to maintain cardiac output (CO). This leads to symptoms of dyspnea, decreased exercise tolerance and fluid retention, including pulmonary congestion and peripheral edema.[1] HF carries an abysmal prognosis with 50% of patients dying within 4 years of diagnosis.[2] Furthermore, patients with advanced stages of HF will often develop cardiac cachexia, a subset of HF patients who have a considerably worse prognosis; that is, a mortality rate of 50% at 18 months compared with 17% among noncachectic patients.[3]
Patients with HF demonstrate changes in neurohormonal system activation such as the sympathetic nervous system and the renin–angiotensin–aldosterone system, which contribute to remodeling processes that worsen overall cardiac function. Therefore, these systems represent targets for medical therapies to abate the maladaptive changes characteristic of chronic HF.[4,5] In addition to the neurohumoral changes, there is increased interest in hormonal dysregulation in patients with HF. Alterations in the growth hormone (GH)/IGF-1 axis and deficiencies in other anabolic hormones such as testosterone have prompted an interest in hormonal therapy for patients with chronic HF.
The current perception of hormone therapy is controversial. With the media scrutiny of anabolic steroids use in competitive sports, the potential adverse effects of supratherapeutic levels, and the risk of certain cancers, hormone therapy is generally approached with caution. Current American College of Cardiology (ACC) and American Heart Association (AHA) guidelines do not recommend hormone therapy in patients with HF outside of replenishing documented deficiencies. We herein review the evidence behind this recommendation, examining both the efficacy and safety of GH/IGF-1 and testosterone supplementation in patients with HF.

Low Testosterone Associated With High Mortality in Men With Coronary Heart Disease (CHD)

Lisa Nainggolan


October 22, 2010 (Sheffield, United Kingdom)— Among men who have coronary heart disease, mortality was doubled in those with low testosterone levels compared with those who had normal levels, a new observational study has shown. Dr Chris J Malkin (Royal Hallamshire Hospital, Sheffield, UK) and colleagues report their findings in Heart. [1]
"This is the fourth epidemiologic study to have shown that low testosterone is a marker of early mortality," senior author Dr Kevin S Channer (Royal Hallamshire Hospital, Sheffield, UK) told heartwire . "But most crucially, it is the first in men with vascular disease; all of the other epidemiologic follow-up studies of testosterone have excluded this patient population."
In an accompanying editorial [2], Drs Ronald CW Ma and Peter CY Tong (Prince of Wales Hospital, Shatin, Hong Kong) describe the history of studies on testosterone and cardiovascular disease and say the new trial "adds to the emerging picture" by making it clear that the link between reduced testosterone and increased mortality extends to subjects with established cardiovascular disease.
Channer says a long-term (5 to 10 years) prospective randomized placebo-controlled trial of testosterone replacement therapy is now needed in patients with heart disease, to assess its effects on mortality: "If you replace the testosterone, can you push that Kaplan-Meier survival curve back to the normal line?"
The editorialists agree. While Ma and Tong say there are some risks from testosterone--it might increase the risk of prostatic diseases and erythrocytosis, and exacerbate sleep apnea--overall, "The encouraging results from clinical studies so far support investigating the effects of testosterone supplementation on cardiovascular disease in larger clinical trials."
20% of Men Were Testosterone-Deficient
To examine the effect of testosterone levels on survival, Malkin et al followed 930 consecutive men with coronary disease referred for angiography for a two-year period from June 2000, with a mean follow-up of almost seven years. The main variables were all-cause and vascular mortality and the presence of testosterone deficiency.
The overall prevalence of biochemical testosterone deficiency was 20.9% using a measure of bioavailable testosterone <2.6 nmol/L; 16.9% using total testosterone <8.1 nmol/L; and using either measure it was 24%.
Adjusted all-cause and vascular mortality was more than doubled among those with low bioavailable testosterone (hazard ratio [HR] 2.2. p<0.0001 for all-cause mortality; HR 2.2, p=0.007 for vascular mortality) compared with those who had normal levels of the hormone.
Low serum testosterone was one of only four variables found to influence time to all-cause and vascular mortality in multivariate analyses (HR 2.27), along with the presence of left ventricular dysfunction (HR 3.85), aspirin therapy (HR 0.63), and beta-blocker therapy (HR 0.45).
"In patients with coronary disease, testosterone deficiency is common and impacts negatively on survival. Prospective trials of testosterone replacement are needed to assess the effect of treatment on survival," the authors conclude.
Testosterone Not Like Female HRT, No Money for a Big Trial
Channer explains that testosterone replacement therapy can be given in a number of ways. Testosterone is not suitable for oral therapy, because "It undergoes high first-pass metabolism through the liver," he explains. But it is available in slow-release injection formulations, as a three-month depot injection, as transdermal patches, and as a gel. He says his team has had some problems with the skin patch because it causes a rash and men tend not to like it, but they have had more success with the three-month depot injections, which they have been able to keep people on for a year. However, "We desperately need some other formulations," he says.
He is keen to stress that testosterone is a whole different ballgame from female hormone replacement therapy: "Men are given testosterone, the same hormone as they make themselves, and we monitor levels and titrate to physiologic levels. This is not like female hormones, where women were given doses of a drug and the physicians didn't know whether they were physiological, super-physiological, or what; it's totally different."
But he does not hold his breath when it comes to a big trial. He and his colleagues have had every request for funding for such a large study turned down, he says, adding: "The problem is that none of the drug companies that make testosterone are big enough to fund such a study, because it would cost millions."
Concerns Dismissed: Testosterone "Like Thyroid Hormone"
Channer also doesn't understand what he sees as reticence from some quarters when testosterone as a potential therapy is discussed. "I've struggled to understand why endocrinologists don’t just accept that replacing testosterone is the same as replacing thyroid hormone, for example, what's the matter with that?"
And he dismisses any concerns arising from a US National Institutes of Health study in elderly men, which was stopped early because testosterone treatment was associated with an increased risk of cardiovascular events; the paper was published in the New England Journal of Medicine earlier this year.
"We were very surprised that NEJM published that paper. The end points were very soft indeed," he comments. "Yes, there were a few more deaths, but these were elderly men and you wouldn't expect in the duration of that study for the testosterone to have had that kind of effect. We've been doing studies for 15 years with testosterone in men with known heart disease, angina, and heart failure, and we haven't had any [serious] adverse reactions."
Neither the authors nor the editorialists report any conflict of interest.
References

Low Testosterone Levels Linked to Alzheimer's Disease in Older Men

Deborah Brauser

October 14, 2010 — The serum level of bioavailable testosterone (BT) can predict risk for Alzheimer's disease (AD) in older men, new research suggests.
Although low levels of BT were associated with the onset of AD, higher levels may offer protective value against the disease, report the researchers, led by Leung-Wing Chu, MD, chief of geriatric medicine at Queen Mary Hospital at the University of Hong Kong.
"The take home message is we should pay more attention to low testosterone, particularly in people who have signs of cognitive impairment," coinvestigator John Morley, MD, professor of gerontology and director of the Division of Geriatric Medicine at Saint Louis University School of Medicine in Missouri, told Medscape Medical News.
"We found that low testosterone did predict a pretty rapid decline in memory and conversion to Alzheimer's," added Dr. Morley. "So this opens up the possibility of using testosterone as a potential treatment in males who are having early memory problems."
However, he noted that the findings should be viewed with some caution. "We thought the same thing was true with estrogen and then the Women's Health Initiative suggested that at least in some subgroups of women estrogen made them worse not better. So until we have further studies, we just don't know for sure. But we do think it's exciting."
The study was published in the October issue of the Journal of Alzheimer's Disease.
Paucity of Research
The researchers write that there have been only "a limited number of prospective cohort studies" on BT or serum free testosterone and AD. Plus, "there is no published information regarding the short-term protective effect of testosterone against the development of AD in late life," they add.
"We're recognizing more and more that sex hormones play a role in multiple parts of the body, but particularly in the thought process," said Dr. Morley.
"In our animal studies, we've shown that testosterone in an animal model of Alzheimer's basically improves memory," he explained. "So we thought it would be interesting to look at a group of males as they were aging to see whether or not low testosterone predicted an increase in Alzheimer's for them. This was particularly important in the people who had mild cognitive impairment, as this is an area where there are no treatments available."
The investigators evaluated a cohort of 153 men older than 55 years (mean age, 72.7 years) who were enrolled between January 2004 and November 2006.
Full physical and neurologic examinations were given at baseline for all participants at the Queen Mary Hospital Memory Clinic.
In addition, cognitive impairment was assessed using the Chinese versions of the Mini-Mental State Examination, AD Assessment Scale-cognitive subscale, and Delayed 10-Word Recall Test.
Also at baseline, morning serum samples of BT, total testosterone (TT), and sex hormone binding globulin (SHBG) were collected and measured, as were samples of apolipoprotein E (ApoE).
At 1-year follow-up, dementia and AD were assessed for all participants using National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria. Those who had developed AD or other types of dementia were also given brain scans.
Rapid Conversion
Results showed that although none of the men had dementia at baseline, 47 (31%) had mild cognitive impairment (MCI).
At the 1-year time point, 10 of these men had converted to dementia and to AD — and 7 of these showed cerebral atrophy.
Significant independent predictors for conversion to AD from MCI, after logistic regression analysis, were lower baseline serum BT level, higher systolic blood pressure (SBP), and elevated levels of ApoE e4.
The adjusted relative risk (RR) of developing AD was 1.04 for baseline SBP and 5.04 for the ApoE e4 genotype. SHBG was not found to be an independent risk factor.
A higher BT level was also an independent protective factor for AD (adjusted RR, 0.22; 95% confidence interval [CI], 0.07 – 0.69).
Finally, there was a significant difference in the serum BT level between the cognitively normal and the MCI subgroups (1.84 ± 0.11 vs 1.14 ± 0.11 nmol/L, P < .05). No significant differences were found between the groups for serum TT and SHBG levels.
"Based on the present data, the magnitude of risk reduction is quite substantial, and 1 nmol/L increase in serum BT level might reduce the risk of AD at 1 year by 78%" (95% CI, 31% – 93%), write the researchers.
Dr. Morley said that the only surprise he had from the overall results was the speed in which the changes occurred. "This was a short, 1-year study, and we saw that those with cognitive impairment and low testosterone had a dramatically rapid conversion to Alzheimer's disease."
The investigators note that further randomized trials are needed "to evaluate the efficacy of physiological but not supra-physiological testosterone replacement therapy" in preventing AD in older men.
For now, "I think clinicians should be looking at testosterone levels in people who have early memory problems. And if they have a set of symptoms and their testosterone is really low, it would not be unreasonable to consider appropriate treatment in some of them," said Dr. Morley.
He reported that the investigative team is now hoping to receive funding to look at "testosterone in people with early memory problems to see whether or not we can slow down the conversion to Alzheimer's."
This study was funded by the SK Yee Medical Foundation of Hong Kong, the Training and Research Assistance Scheme of the Queen Mary Hospital Charitable Trust, and the University of Hong Kong Alzheimer's Disease Research Network of SRT on Healthy Aging. In addition, Organon provided some funding for the original study. Dr. Morley provides or has provided consultation for Organon, Mattern Pharmaceuticals, and Solvay & Schering.
J Alzheimers Dis. 2010;21:1335-1345.

From Reuters Health Information

Fatherhood Lowers Testosterone in Men, Study Finds

By Julie Steenhuysen
CHICAGO (Reuters) Sep 12 - Fatherhood lowers testosterone levels, U.S. researchers said they have confirmed, making it easier for men to be involved in raising children.
High levels of the hormone can rev up a man's sex drive, increase risk-taking behaviors and raise the need for social dominance. Those factors can help win a mate but are poor traits when it comes to raising a baby, which requires cooperation from both parents.
"Our study shows that human fathers are biologically wired to help with the job," said Christopher Kuzawa of Northwestern University, who worked on the study published in the Proceedings of the National Academy of Sciences.
Prior studies have shown fathers tend to have lower testosterone than men who have no children but it was not clear whether fatherhood was the cause or that men with lower testosterone were more likely to become fathers.
The Northwestern study tried to answer that question by following a group of more than 600 men from the Philippines over five years. The men were not fathers at the start of the study.
The team saw clearly that right after the men became fathers, their testosterone levels dropped, at least for a short time.
"It's not the case that men with lower testosterone are simply more likely to become fathers," Lee Gettler of Northwestern University, who worked on the study, said in a statement.
"On the contrary, the men who started with high testosterone were more likely to become fathers, but once they did, their testosterone went down substantially."
Gettler said the findings suggest fathers may experience an especially large but temporary drop in testosterone when they first bring home a newborn baby.
"Fatherhood and the demands of having a newborn baby require many emotional, psychological and physical adjustments," Gettler said. "Our study indicates that a man's biology can change substantially to help meet those demands."
Dr. Allan Pacey of the University of Sheffield said testosterone levels in men generally do not change much.
"They can slowly decline as men get older and change in response to some medical conditions and treatment. But to see dramatic changes in response to family life is intriguing." he said in a statement.
Professor Ashley Grossman, a professor of endocrinology at the University of Oxford, said endocrinologists tend not to pay much attention to men's testosterone levels, as long as they are in the normal range.
"Life and biology may be much more subtle and adaptable than we had previously thought," he said.
SOURCE: http://bit.ly/q2Hq5b