Experts recommend against diagnosing testosterone deficiency in women

The Endocrine Society today issued a Clinical Practice Guideline (CPG) advising against the use of testosterone therapy in healthy women.

06 oct 2014--The CPG, entitled "Androgen Therapy in Women: A Reappraisal: An Endocrine Society Clinical Practice Guideline," was published online in the Journal of Clinical Endocrinology and Metabolism (JCEM), a publication of the Endocrine Society. The Society updated its 2006 recommendations to address new research concerning testosterone and dehydroepiandrosterone (DHEA) therapy in women as well as advances in testosterone testing and measurement techniques.

Androgens are a group of sex hormones that includes testosterone. DHEA is a prohormone that can be converted into testosterone or estradiol, a form of estrogen. While these are often thought of as male hormones, small amounts of androgens also are found in women.

"Although limited research suggests testosterone therapy in menopausal women may be linked to improved sexual function, there are too many unanswered questions to justify prescribing testosterone therapy to otherwise healthy women," said Margaret E. Wierman, MD, of the University of Colorado in Aurora, CO. She also is the Society's Vice President of Clinical Science and chair of the task force that authored the guideline.

"When we reviewed past studies, we found many women who had low testosterone levels measured by older or new techniques did not exhibit any signs or symptoms of concern," Wierman said. "As a result, physicians cannot make a diagnosis of androgen deficiency in women."

This is different from men, who often display specific symptoms of androgen deficiency. In cases where men have both symptoms and low levels of testosterone, they can be diagnosed with hypogonadism, according to the Society's Clinical Practice Guideline on Testosterone Therapy in Adult Men with Androgen Deficiency Syndromes.

For women, the only situation where the Society suggests prescribing testosterone therapy is if a woman has been diagnosed with Hypoactive Sexual Desire Disorder (HSDD). This condition occurs when a woman has no interest in sex and that lack of interest causes personal distress. In these cases, the CPG suggests a three- to six-month trial of testosterone to see if the therapy improves sexual function.

Some physicians opt to prescribe testosterone therapy to otherwise healthy women on an off-label basis. The CPG recommends that physicians avoid prescribing testosterone to improve sexual dysfunction in women who do not have HSDD. Use of testosterone in women has been linked to changes in cholesterol as well as conditions like acne and hirsutism, the excessive growth of hair, often on the face, back or chest. Long-term risks to the breast or cardiovascular system are unknown.

"Currently, there isn't enough evidence that any benefits outweigh the risks to most women," Wierman said. "More research is needed to determine the long-term safety of testosterone therapy in postmenopausal women."

Review of the use of DHEA therapy showed no significant benefit when given to normal women or those with adrenal insufficiency. As a result, the task force did not recommend treatment of women with DHEA.

Since the publication of the Society's 2006 CPG, there have been significant advances in testosterone testing and measurement. Now more research is needed to reexamine existing theories about the role of testosterone in women and answer ongoing questions about its safety and effectiveness, Wierman said.

To ensure hormone levels are measured accurately, the test must be carefully calibrated. The Society collaborated with the Centers for Disease Control and other groups to establish the Partnership for the Accurate Testing of Hormones (PATH) to address the need for better hormone testing.

Provided by The Endocrine Society

More testosterone increases prostate cancer risk in older men: study

26 july 2012-- Older men - those in their 70s and 80s - with higher levels of testosterone, including those who undergo hormone replacement therapy, are at an increased risk of prostate cancer, according to new research.  

Results from Australia's largest healthy ageing study, The Health in Men Study (HIMS), published online today in the peer reviewed journal, Cancer Epidemiology Biomarkers & Prevention, have confirmed this link.

Lead author from The University of Western Australia's Centre for Health and Ageing, Dr Zoë Hyde, said while higher levels of testosterone were unlikely to cause cancer, they might make an existing cancer grow faster. 

However, Dr Hyde cautioned that this did not prove a cause-and-effect relationship.

"We need to conduct large-scale long-term trials of testosterone therapy to see if this risk applies to men receiving testosterone," she said.

The research is timely because the use of testosterone therapy is growing, and prostate cancer is very common in old age, Dr Hyde said.

Low testosterone in older men can cause loss of muscle mass, decreased sexual function, fatigue, mood changes, depression and impaired cognition. Hormone replacement therapy may seem the best approach to relieve the symptoms, but scientists now believe more research is needed on this treatment to determine if it does help patients.

They say the possibility that high levels of testosterone could make prostate cancer grow faster is concerning.  A cancer that would have gone undetected and never caused any problems might now affect health.

"While some men can benefit from testosterone therapy, we still don't fully understand all of the benefits and risks of treatment," Dr Hyde said.

"There is no need for men who are currently taking testosterone to stop but in light of our findings, prostate health should be monitored closely during treatment."

This research is part of the Health In Men Study that has been following a group of men living in Perth, Western Australia, since 1996 and is the largest study of ageing men in Australia.  The study involved community-dwelling men in their 70s and 80s but excluded those receiving hormonal therapy or men with prostate cancer.

More information: cebp.aacrjournals.… .EPI-12-0129

Provided by University of Western Australia

Testosterone overprescribed, particularly for older men

07 jun 2012-- Testosterone prescriptions have surged since 2006 due to promotional activity, according to University of Sydney research which also found growing overuse in older men.
The research by Professor David Handelsman from the University and director of the ANZAC Research Institute, Concord Hospital has been published today in the Medical Journal of Australia.
It follows another recent study, led by Professor Handelsman and published in the journal of Clinical Endocrinology, which suggests testosterone decline in older men is not a result of ageing but of medical conditions and ill health that accumulate as men get older.
"This Healthy Man Study looked at very healthy men aged 40 and over and found that a decrease in testosterone was not associated with increasing age. Instead factors such as obesity or a history of smoking were strongly linked with any decrease," Professor Handelsman said.
The study supported the interpretation that diseases associated with ageing and not ageing itself affects testosterone levels in older men. It underlines the inappropriateness of the increasing sales of testosterone to older men which is highlighted in Professor Handelsman's MJA article.
The study in the MJA analyses data from the Pharmaceutical Benefits Scheme and IMS, a company that provides national sales data year by year.
"I found that stable market growth over 15 years was disrupted by sharp increases following the introduction of two new testosterone products - a gel and a long-acting injectable version by a single company which became a monopoly supplier," Professor Handelsman said.
"There is growing overuse of testosterone in older men as an anti-ageing tonic and non-specific treatment for sexual dysfunction, for which sound evidence is lacking. Yet at the same time genuine low-testosterone conditions due to diseases of the reproductive system remain underdiagnosed."
At present new uses of testosterone should be restricted to carefully designed clinical trials to determine whether there is any objective benefit from testosterone treatment for conditions such as obesity, diabetes or cardiovascular diseases that accumulate as men age, Professor Handelsman observed.
"The progressive increase appears to be due to promotion-driven marketing of products which do not comply with the Pharmaceutical Benefits Scheme prescribing criteria and suggest that more effective implementation of those criteria is needed."
Provided by University of Sydney

Study refutes testosterone as 'fountain of youth'

A new study of older Western Australian men has revealed that testosterone might not be the fountain of youth.

23 oct 2011--Published online this week in the Journal of Clinical Endocrinology and Metabolism, researchers from The University of Western Australia's Western Australian Centre for Health and Ageing set out to explore the association between testosterone levels and cause of death.

They confirmed earlier studies suggesting that men with low testosterone were more likely to die of cardiovascular disease.

But lead author and WA Centre for Health and Ageing researcher Zoë Hyde said low testosterone levels were not linked to death from other diseases, which was surprising.

"Previous studies suggested that men with low testosterone levels are likely to die earlier, and some researchers have argued that testosterone therapy might improve longevity," Ms Hyde said.

"However, our results suggest that low testosterone is a risk factor only for cardiovascular disease, and do not provide support for more widespread use of testosterone."

Testosterone therapy is available in Australia only for men whose levels have been found to be low on testing and are experiencing symptoms of testosterone deficiency.

Ms Hyde said it was premature to recommend testosterone therapy to prevent cardiovascular disease.

"Although our study suggests that preventing testosterone deficiency might have some health benefits, we need to first conduct clinical trials of testosterone therapy to see if these findings are real, and to also properly evaluate the risks of therapy," she said.

Ms Hyde said sex hormones played an important role in maintaining health and quality of life, particularly as their concentrations changed over time.

The research forms part of the Health In Men Study (HIMS) that has been following a group of men living in Perth, Western Australia since 1996 and is the largest study of ageing men in Australia. It involves community-dwelling men aged in their 70s and 80s but excludes men receiving hormonal therapy or men with prostate cancer.

Provided by University of Western Australia

Older age does not cause testosterone levels to decline in healthy men

A decline in testosterone levels as men grow older is likely the result—not the cause—of deteriorating general health, say Australian scientists, whose new study finds that age, in itself, has no effect on testosterone level in healthy older men.

09 june 2011--The results, to be presented Tuesday at The Endocrine Society's 93rd Annual Meeting in Boston, are the first findings released from the Healthy Man Study, according to principal investigator David Handelsman, MD, PhD, professor and director of the ANZAC Research Institute at the University of Sydney.

"Some researchers believe that an age-related testosterone deficiency contributes to the deteriorating health of older men and causes nonspecific symptoms, such as tiredness and loss of libido," he said.

Handelsman and his team, however, found that serum (blood) testosterone levels did not decline with increasing age in older men who reported being in excellent health with no symptoms to complain of.

"We had originally expected age to have an effect on serum testosterone, so the findings were a bit of a surprise," Handelsman said.

Two study centers in Australia recruited 325 men over the age of 40 (median age, 60) who had self-reported excellent health and no symptom complaints. To test blood testosterone levels, the researchers took blood samples from the men nine times over three months. They excluded men from the study who took medications that affect testosterone.

Obesity caused a mild and clinically unimportant lowering of blood testosterone levels, the investigators reported. Age had no effect on testosterone level.

"The modest decline in blood testosterone among older men, usually coupled with nonspecific symptoms, such as easy fatigue and low sexual desire, may be due to symptomatic disorders that accumulate during aging, including obesity and heart disease," he said. "It does not appear to be a hormone deficiency state."

The message for patients and their doctors, Handelsman said, is "older men with low testosterone levels do not need testosterone therapy unless they have diseases of their pituitary or testes."

Provided by The Endocrine Society

Short-Term Testosterone Has Limited Effects in Aging Men

By Charles Bankhead
UTRECHT, Netherlands, Jan. 2 -- A daily dose of testosterone increased lean body mass, produced mixed metabolic effects, and had no effect on functional or cognitive status in older men, investigators here found.
Action Points --->
Explain to patients that testosterone supplementation improved lean body mass in older men but did not improve functional status or cognition.
Note that multiple studies of testosterone supplementation have yielded inconsistent results.
During six months of treatment, lean body mass increased and fat mass decreased in the testosterone group compared with the placebo group (P<0.001), Marielle H. Emmelot-Vonk, M.D., of the University of Utrecht, and colleagues reported in the Jan. 1 issue of the Journal of the American Medical Association.
Insulin sensitivity improved but HDL-cholesterol decreased and, by study end, the proportion of men meeting diagnostic criteria for metabolic syndrome trended higher in the testosterone group (47.8% versus 35.5%, odds ratio: 1.7, 95% CI: 0.97 to 2.8, P=0.07).
"The findings in this study do not support a net benefit on several indicators of health and functional and cognitive performance with six months of modest testosterone supplementation in healthy men with circulating testosterone levels in the lower range," the authors concluded.
The inconsistency of previous clinical trials of testosterone supplementation likely reflects differences in study design, the type and duration of treatment, and instruments employed to study aging, Dr. Emmelot-Vonk and colleagues stated.
Moreover, most studies had small sample sizes that limited power to detect differences in effects, and studies have had a limited scope, assessing only one or two aging-related outcomes, the authors continued.
The Institute of Medicine noted those limitations and other shortcomings in calling for more short-term, randomized, placebo-controlled clinical trials to examine the safety and efficacy of testosterone supplementation in aging men (National Academies Press, 2004).
So Dr. Emmelot-Vonk and colleagues conducted a blinded, randomized, placebo-controlled trial of testosterone supplementation in 237 healthy men ages 60 to 80. All study participants had testosterone levels <13.7 nmol/L and fell within the range of low-normal.
The men were randomized to 80 mg of testosterone twice daily for six months or a matching placebo regimen. All but 30 of the men completed the study.
Investigators examined the effects of testosterone supplementation on multiple outcomes: functional mobility (multiple tests), cognitive function (eight different tests), bone mineral density, body composition, metabolic risk factors, quality of life, and safety parameters.
Cognitive function and bone density did not change in the testosterone group relative to the placebo group.
Glucose, insulin, insulin sensitivity, and insulin resistance all improved significantly in the testosterone group compared with the placebo group (P=0.04 to P=0.007). However, HDL-cholesterol decreased from 1.2 mmol/L to 1.0 mmol/L in the testosterone group and remained unchanged in the placebo group (P<0.001).
The ratio of total cholesterol to HDL also was significantly higher in the men who received daily testosterone (P<0.001).
Quality-of-life measures did not differ between groups, and investigators found no evidence of a negative effect of testosterone in prostate safety.
Addressing limitations of the study, Dr. Emmelot-Vonk and co-authors acknowledged the brief period of follow-up, but they noted that other studies had demonstrated significant changes in outcomes within six months.
Additionally, they said, effects on supplementation should have been evident within six months for all but one of the endpoints chosen for the study (bone mineral density).
The testosterone dose used in the study was consistent with doses used in previous trials, they added. And, although testosterone levels in the blood did not increase among participants receiving the hormone, that was the experience in other studies as well.
"This study is, as far as we know, the largest study of testosterone supplementation with the most endpoints and a randomized, double-blind design," the investigators concluded. "Adherence was high and the dropout rate was low."
The study was supported by the Netherlands Organization for Health Research and Development and by Organon.
The authors reported no financial disclosures.
Primary source: JAMASource reference:Emmelot-Vonk MH, et al "Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men" JAMA 2008; 299: 39-52.

Low Testosterone Levels Indicate Increased Risk of CV Death in Men

November 30, 2007 — High endogenous levels of testosterone in men are associated with low mortality from all causes, cardiovascular causes, and cancer, a new study shows, and the authors suggest that low testosterone may be a predictive marker for those at high risk of cardiovascular disease [1].
The study, published online November 26, 2007 in Circulation, found an inverse relation between endogenous testosterone concentrations and mortality due to cardiovascular disease, cancer, and all causes.
Lead author Dr Kay-Tee Khaw (University of Cambridge School of Clinical Medicine, UK) commented to heartwire: "This is the largest study of testosterone levels ever conducted. We don't know whether the association shown between higher levels of testosterone and lower mortality is causal or just a marker of something else, but regardless of this, it appears that low testosterone levels do identify a group at increased risk of cardiovascular death who could benefit from more aggressive treatments in terms of cholesterol and blood-pressure lowering."
Prostate cancer risk not increased
She added that it was far too soon to be recommending testosterone supplementation, but this study should ease the concerns that have prevented studies of such interventions from being conducted. She explained: "There has been a worry that testosterone supplementation may increase the risk of prostate cancer, but we did not see any more cases of prostate cancer in men with higher testosterone levels compared with those with lower levels. This is reassuring and should open the way for studies of testosterone supplementation in men with low levels to take place."
She said that research into raising testosterone levels in men has also been hampered somewhat by the negative results with estrogen replacement in women. "The observational studies of estrogen replacement in women were encouraging, but randomized controlled trials actually showed harm. That has put people off the idea of hormone therapy in men as well. But the observational studies in women were mainly with estrogen supplements and suffered from many biases, as women who took estrogen supplements were different in many other ways from women who didn't. In contrast, our study in men looked at endogenous testosterone levels, which should have fewer biases," Khaw said.
Improved CV risk profile
In the paper, Khaw and her colleagues note that the role of testosterone in men's health is controversial. High doses of exogenous testosterone or other anabolic steroids have been associated with adverse health effects, including sudden cardiac death and liver disease, but hypogonadism in men is also adversely associated with health, and the use of lower doses of exogenous testosterone is increasingly widespread because of the belief that supplementation has benefits for well-being. They add that high endogenous testosterone concentrations in men are associated with a more favorable cardiovascular disease risk-factor profile, including higher high-density lipoprotein (HDL) levels and lower blood pressure, triglycerides, and glucose concentrations, but prospective studies to date have not found significant relationships between endogenous testosterone concentrations and cardiovascular disease events. In addition, high endogenous testosterone concentrations have been postulated to be a risk factor for prostate cancer, although again, prospective studies have found no consistent relationships.
Noting that most of these studies have had limited power for disease events, they analyzed data on testosterone levels from the large European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk) population study conducted between 1993 and 2003. They examined the prospective relationship between endogenous testosterone concentrations and mortality due to all causes, cardiovascular disease, and cancer in a nested case-control analysis of the 11 606 men who participated in the study. Among those without cancer or cardiovascular disease at baseline, 825 men who subsequently died were compared with a control group of 1489 men still alive, matched for age and date of baseline visit. Of the 825 deaths in the study, 369 were attributed to cardiovascular disease and 304 to cancer.
Results showed that endogenous testosterone concentrations at baseline were inversely related to mortality due to all causes, cardiovascular disease, and cancer.
Results have been adjusted for age, covariates (date of visit, body-mass index, systolic blood pressure, blood cholesterol, cigarette smoking, diabetes, alcohol intake, physical activity, social class, education), and other hormone levels
Compared with men who had testosterone levels of 12.5 nmol/L or less, men with testosterone levels of at least 19.6 nmol/L had a 41% lower risk of dying in 10 years. For every 6-nmol/L increase in endogenous testosterone, the risk of death decreased 14%.
The authors say that although they cannot exclude residual confounding from other factors not measured here, "these findings are consistent with existing evidence from epidemiological and clinical studies indicating that endogenous testosterone concentrations may be an indicator of good health." The link between testosterone and mortality could provide insights and better understanding of disease mechanisms and hence the possibility of new therapeutic pathways, they comment.
But they caution that that these results require replication in other population studies, adding that the adverse results of hormone replacement therapy (HRT) trials in women emphasize the necessity for end-point trials. They note that paradoxically, although many men are already using testosterone supplementation, concern about increased cancer risk has been one reason trials have not been conducted in this area. But now data from this study should encourage further research into the role of testosterone in health in men, they conclude.
Source
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; DOI: 10.1161/CIRCULATIONAHA.107.719005. Available at: http://circ.ahajournals.org.