testosterone, again

there have been a couple of recent articles on testosterone, though please note the older blog from 4/3/14, appended below. 

1. article in j clin endocrinology and metabolism on testosterone therapy for men with type 2 diabetes (T2D) and low testosterone levels (see dm testosterone not help sex jcem 2014​ in dropbox, or doi: 10.1210/jc.2014-1872). 88 men aged 35-70 (ave age 62) with A1c <8.5%, total testosterone (TT) < 346 ng/dl (they specifically were looking for men with low normal testosterone levels, and excluded those with TT < 144), with mild to moderate"aging male symptoms" and erectile dysfunction, randomized to 40 weeks of IM testosterone undecanoate 1000 mg or placebo, assessing their AMS (aging male symptoms score, a validated 17-item scale to assess 3 domains: somatovegetative, psychological, and sexual), as well as sexual desire and erectile function. this analysis was a secondary one, with the primary study finding in these men that testosterone injections did not lead to any change in glucose metabolism (insulin resistance or glycemic control) or visceral adiposity (for that study see: Diabetes Care 2014;37:2098–2107). results of current analysis:
    --testosterone injections did in fact increase TT levels
    --no difference in the AMS score with testosterone injections
    ​--no difference in sexual desire (interestingly, those on IM testosterone actually had reduced erectile function)
    --although the utility of free testosterone levels is debated, they found that 72% of the men had low free testosterone and there was no difference in results for them vs those with low TT
    --symptoms overall were worse at baseline if men were depressed or if had microvascular complications (neither of these correlated with TT levels)
    --the authors are careful to note that their conclusions do not apply to symptomatic men with unequivocally low testosterone levels, and that their results for men with less severe androgen deficiency were somewhat at odds with some other studies

Note: 30-50% of aging, obese men with T2D have low TT, though the vast majority have only mildly decreased TT (as in this study). in observational studies, 55-70% of those with low TT levels have symptoms of androgen deficiency, but 50-55% of those with normal TT had similar symptoms. so, i think this study is relevant to us because it highlights the importance (and high prevalence) of depression as a likely cause of sexual dysfunction, and the lack of significant efficacy of testosterone therapy. The data for clinical benefit of  testosterone therapy in older men is very mixed, with best data for improving libido, though no significant change in erectile function or sexual satisfaction. As a result,  the Institute of Medicine's committee on testosterone concluded that there is insufficient evidence to recommend that testosterone treatment of older men has any well-established benefit. the number of testosterone prescriptions has increased dramatically in the last several years -- this study reinforces the lack of real utility for testosterone replacement therapy for the majority of men (with the exception of those with profound TT deficiency, eg a man with symptoms consistent with testosterone deficiency -- eg decreased libido, mood, osteoporosis, energy plus a TT level measured between 8-10AM and less than 300 ng/dL, and this test should be repeated/confirmed 2x more before giving meds since there are significant daily variations in TT). and there are real risks to testosterone therapy, as noted in the 4/3/14 blog below.

2. the Endocrine Society came out with a clinical practice guideline for androgen therapy in women (see androgen therapy in women guidelines JCEM2014 in dropbox, or doi: 10.1210/jc.2014-2260). they basically recommend:
    --do not diagnose androgen deficiency in healthy women because of lack of well-defined syndrome and lack of data correlating symptoms with androgen levels. and don't use testosterone routinely in those with hypopituitarism, adrenal insufficiency, etc.
    --do not use testosterone therapy for infertility; sexual dysfunction (other than "hypoactive sexual desire syndrome", which studies suggest may respond to short term testosterone therapy, though endogenous testosterone levels do not predict response to therapy even in this "syndrome"); cognitive, cardiovascular, metabolic, or bone health; or general well-being
    --not use dehydroepiandrosterone​
    --AND, none of these testosterone preparations are available in the US for women, women frequently develop very high serum testosterone levels on therapy, and long-term safety data are lacking (though it seems that the testosterone equivalent doses for women is about 10% of those used in men).

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blog from 4/3/14:

here is the Jan 31 FDA alert about testosterone (also see link: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm384225.htm):

AUDIENCE: Cardiology, Urology, Family Practice

ISSUE: FDA is investigating the risk of stroke, heart attack, and death in men taking FDA-approved testosterone products. We have been monitoring this risk and decided to reassess this safety issue based on the recent publication of two separate studies that each suggested an increased risk of cardiovascular events among groups of men prescribed testosterone therapy. FDA is providing this alert while it continues to evaluate the information from these studies and other available data. FDA will communicate final conclusions and recommendations when the evaluation is complete.

BACKGROUND: Testosterone is a hormone essential to the development of male growth and masculine characteristics. Testosterone products are FDA-approved only for use in men who lack or have low testosterone levels in conjunction with an associated medical condition.

RECOMMENDATION: At this time, FDA has not concluded that FDA-approved testosterone treatment increases the risk of stroke, heart attack, or death. Patients should not stop taking prescribed testosterone products without first discussing any questions or concerns with their health care professionals. Health care professionals should consider whether the benefits of FDA-approved testosterone treatment is likely to exceed the potential risks of treatment. The prescribing information in the drug labels of FDA-approved testosterone products should be followed.

i just sent out one of the studies (from PLoS) last week, the other one being a recent one in JAMA (see testosterone and mortality jama 2013, or doi:10.1001/jama.2013.280386). in the jama study they looked retrospectively of 8700 men in the VA with low testosterone levels (<300 ng/dL) who had coronary angiography in the years 2005-2011. findings:

--1223 of these men started testosterone an average of 531 days after cath (20% with prior hx MI, 50% with diabetes, 80% with known CAD). those on testosterone tended to be younger and have fewer comorbidities. the testosterone levels were also lower (176) in those put on testosterone therapy vs those not (207)

--after 3 years, those who were on testosterone: 25.7% had an event (all-cause mortality, MI, or stroke) vs 19.9% not on testosterone, finding a 29% increase in events in those on testosterone. no relation between those with or without coronary artery disease. (unlike some prior studies, the increase in events did not happen soon after starting testosterone, but after 3 years). no diff in the VA group with baseline cardiovasc risk factors in those who had/did not have events.

speculated mechanisms for testosterone and cardiovasc disease: testosterone increases platelet thromboxane A2 receptor density and platelet aggregation; dihydrotestosterone (a metabolite) increases smooth muscle proliferation and expression of vascular cell adhesion molecule 1;testosterone worsens sleep disordered breathing in those with OSA. (all of these are potentially directly assoc with cardiovasc dz)

so, nothing definitive, and the FDA alert is an alert, albeit a lukewarm one. but my sense is that there are enough data to reinforce being wary, at least only prescribing testosterone if there is a clear clinical indication, and letting patients know that there is a potential link.​