Androgen Replacement

Gettman MT. The Impact of Testosterone Therapy in Men on Cardiovascular Risk: Don't Be Too Quick to Condemn. Mayo Clin Proc. http://www.mayoclinicproceedings.org/article/S0025-6196(14)01087-8/fulltext

In this issue of Mayo Clinic Proceedings, Morgentaler et al1 provide a timely update regarding testosterone therapy in men and cardiovascular risk. This review is important considering the recent controversy claiming increased cardiovascular risk in men receiving testosterone therapy. Morgentaler et al identified 4 studies suggesting that testosterone therapy increases the risk of cardiovascular events, but they also identified more than 100 studies demonstrating that normal testosterone levels (and, accordingly, physiologic replacement of testosterone) provide beneficial effects to men and minimize cardiovascular risk and mortality.1, 2, 3, 4, 5 They also critically evaluated the 4 positive studies and noted that 2 studies had serious methodology concerns, 1 was a meta-analysis with poor inclusion criteria, and 1 was a placebo-controlled study with too few cardiovascular events to make definitive conclusions.2, 3, 4, 5

Morgentaler et al are not alone when it comes to concerns raised about the recent studies reporting adverse cardiovascular effects of testosterone. For example, the methodology concerns in the report by Vigen et al3—one of the reports suggesting harm by testosterone—have been so great that 29 professional societies, including the International Society for Men’s Health, the International Society of Sexual Medicine, and the Sexual Medicine Society of North America, have demanded that the article be retracted.1

In the present review, Morgentaler et al stress that cardiovascular mortality and incident coronary artery disease are associated with lower levels of total testosterone, free testosterone, and bioavailable testosterone. In a study by Ohlsson et al,6 for example, men with serum total testosterone concentration levels of 550 ng/dL or more (ie, the highest quartile) had a 30% lower risk of cardiovascular events than did men in the 3 lower quartiles, even after adjusting for traditional cardiovascular risk factors and excluding men with known baseline cardiovascular disease.6 At first glance, these are somewhat paradoxical observations considering the recent inquires by the Food and Drug Administration (FDA), a call for more stringent product labeling, and an outcry in the lay press that testosterone therapy is hazardous.

Multiple studies in men have shown that having normal blood testosterone concentrations help promote normal cardiovascular health. Testosterone therapy is associated with not only decreasing obesity and waist circumference but also improving glycemic control.7 Such studies give credence to the notion that testosterone therapy (to restore normal testosterone physiology) should be heart healthy. In the report, Morgentaler et al note in randomized trials in men with heart failure and coronary artery disease that testosterone therapy appears to improve cardiovascular function.1 Indeed, the largest meta-analysis to date—that is, one involving 75 studies and 5464 patients—reported that testosterone therapy did not increase cardiovascular risk but instead decreased cardiovascular risk among those with metabolic syndrome.8

The importance of having a normal blood testosterone concentration to prevent cardiovascular risk can also be inferred from studies looking at the effect of androgen deprivation therapy as a treatment for prostate cancer. Keating et al9 evaluated 73,196 men with prostate cancer and examined the risk of cardiovascular events associated with the administration of any androgen deprivation therapy. They reported that androgen deprivation therapy significantly increased the risk of diabetes mellitus, coronary heart disease, myocardial infarction, and sudden cardiovascular death.9

Despite the few recent reports suggesting otherwise and negative media attention, testosterone therapy is safe and effective when used responsibly.10, 11 Starting in the 1940s and 1950s, testosterone therapy has an excellent track record for improving quality of life for men diagnosed with hypogonadism. Testosterone therapy is indicated only when men have low serum testosterone levels documented in the setting of associated symptoms and signs of hypogonadism. Importantly, testosterone therapy is not indicated for men with low or low to normal testosterone levels without the signs and symptoms of hypogonadism. Testosterone therapy is also not indicated to treat symptoms suggestive of hypogonadism in the absence of documented low testosterone levels.11 Indeed, the decision to start testosterone therapy requires not only a bona fide hypogonadism diagnosis but also shared decision making with men and their health care providers discussing the potential risks of treatment, required surveillance testing during treatment (serum testosterone, prostatic-specific antigen, and hematocrit assessments), and assessment of adverse effects and other risks (eg, prostate cancer, benign prostatic hyperplasia, sleep apnea, and venous thrombosis) that may warrant discontinuation of treatment. Laboratory testing should be done 3 months after initiating treatment and ongoing monitoring continued even after stability of replacement is achieved (at 6- to 12- month intervals). While on therapy, laboratory targets would be serum testosterone concentrations of 400 to 700 ng/dL, hematocrit level not above the upper limit of normal, and prostatic-specific antigen level maintained within age-adjusted ranges and not associated with worrisome velocity trends (0.4 ng/mL/y over ≥2 y) or significant yearly increases (>50%).

The recent controversy about testosterone therapy has engendered concern from the FDA regarding treatment safety.12, 13 On September 17, 2014, the FDA convened an advisory panel to discuss the potential risk of major adverse cardiovascular events associated with testosterone therapy and the appropriate patient population for whom testosterone therapy should be prescribed. Ultimately, the panel voted 20-1 for the FDA to impose stricter limitations on the testosterone drug industry and tightened labeling information regarding testosterone therapy’s effects on libido, fatigue, and muscle loss. The panel also concluded that evidence linking testosterone therapy to increased risk of cardiovascular events is “inconclusive.” In this regard, the panel voted 20-1 recommending that pharmaceutical companies further study cardiovascular effects of testosterone therapy.12 Although some may question the FDA’s conclusion that the association between testosterone therapy and cardiovascular events is inconclusive, especially considering a large amount of data suggesting otherwise, there appear to be other agendas (see below) that the FDA would also like to be addressed.

Indeed, this approach by the FDA appears prudent considering the current state of testosterone therapy. Since the early 2000s, the use of testosterone therapy has quadrupled.13 This increase in prescriptions potentially has been driven by better formulations for testosterone delivery as well as a direct-to-consumer marketing campaigns that suggest that testosterone therapy may in essence represent a new “fountain of youth.” When testosterone therapy was administered solely with a needle with a more labor-intensive dosing regimen of every couple of weeks in physicians’ offices, the treatments tended to be used exclusively by those who absolutely were in need of replacement therapy. As the mode of administration of testosterone therapy has become easier, and more pharmaceutical industry resources have been directed at convenient product development, we have started seeing not only “low T” commercials on television but also the number of testosterone therapy prescriptions increasing dramatically. Although Morgentaler et al1 point out that testosterone therapy has not been a top target of direct-to-consumer marketing, it seems that the use of direct-to-consumer marketing has been effective. For instance, it was estimated in 2013 that 2.3 million American men were receiving testosterone therapy. Alarmingly, it was also estimated that up to 25% of them received a prescription without having a baseline testosterone level documenting hypogonadism.13 At the very least, the increased attention to the testosterone treatment debate will hopefully impose stricter prescribing requirements for men seeking testosterone therapy and better regulation of the pharmaceutical companies marketing testosterone therapy.

One may ask why the publication of a few recent studies with well-delineated methodology concerns captured intense media attention and the attention of the FDA. The answer is likely multifactorial. It may be based in general on society’s increasing interest in health and wellness and the public’s notion that testosterone treatment was essentially “risk-free.” It may be based on the fact that changing demographics suggest that millions more men may potentially qualify for treatment in the future (with unnecessary patient risk and cost of therapy) unless treatment effects are better characterized. It may also be related to concerns about overtreatment or mistreatment because the availability, marketing, and delivery of testosterone therapy have increased. Indeed, in the setting of increased public concern and heightened media attention, the comprehensive work by Morgentaler et al provides some needed reassurance that testosterone therapy appears safe, at least from a cardiovascular standpoint, as we regroup to comprehensively evaluate the global safety, risks, and efficacy of this treatment in men.

References

1. Morgentaler, A., Miner, M., Caliber, M. et al. Testosterone therapy and cardiovascular risk: advances and controversies. Mayo Clin Proc. 2014; 90 (xx-xx). http://www.mayoclinicproceedings.org/article/S0025-6196(14)00925-2/fulltext

2. Finkle, W.D., Greenland, S., Ridgeway, G.K. et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PloS One. 2014; 9: e85805. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0085805

3. Vigen, R., O’Donnell, C.I., Baron, A.E. et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013; 310: 1829–1836. http://jama.jamanetwork.com/article.aspx?articleid=1764051

4. Xu, L., Freeman, G., Cowling, B.J., and Schooling, C.M. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med. 2013; 11: 108. http://www.biomedcentral.com/1741-7015/11/108

5. Basaria, S., Coviello, A.D., Travison, T.G. et al. Adverse events associated with testosterone administration. N Engl J Med. 2010; 363: 109–122. http://www.nejm.org/doi/full/10.1056/NEJMoa1000485

6. Ohlsson, C., Barrett-Connor, E., Bhasin, S. et al. High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. J Am Coll Cardiol. 2011; 58: 1674–1681. http://content.onlinejacc.org/article.aspx?articleid=1146860

7. Srinivas-Shankar, U., Roberts, S.A., Connolly, M.J. et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2010; 95: 639–650. http://press.endocrine.org/doi/abs/10.1210/jc.2009-1251

8. Corona, G., Maseroli, E., Rastrelli, G. et al. Cardiovascular risk associated with testosterone boosting medications: a systematic review and meta-analysis. Exp Opin Saf Drug. 2014; 13: 1327–1351. http://informahealthcare.com/doi/abs/10.1517/14740338.2014.950653

9. Keating, N.L., O’Malley, A.J., and Smith, M.R. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol. 2006; 24: 4448–4456. http://jco.ascopubs.org/content/24/27/4448

10.Endocrine Society. Endocrine Society calls for large-scale studies to evaluate testosterone therapy risks. Available at: https://www.endocrine.org/news-room...tudies-to-evaluate-testosterone-therapy-risks. Accessed August 31, 2014.

11. American Urological Association. AUA position statement on testosterone therapy. Available at: https://www.auanet.org/about/testosterone-therapy.cfm. Accessed October 17, 2014.

12. American Urological Association. Testosterone – FDA. Available at: http://www.auanet.org/common/pdf/advocacy/advocacy-by-topic/Testosterone-FDA.pdf. Accessed October 17, 2014.

13.Food and Drug Administration. Joint meeting for Bone, Reproductive and Urology Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management Advisory Committee (DSARM AC), September 17, 2014. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM412536.pdf. Accessed October 24, 2014.
 
Freedman J, Glueck CJ, Prince M, Riaz R, Wang P. Testosterone, thrombophilia, thrombosis. Transl Res. https://www.sciencedirect.com/science/article/pii/S1931524414004678

We screened previously undiagnosed thrombophilia (V Leiden-prothrombin mutations, Factors VIII and XI, homocysteine, and antiphospholipid antibody [APL] syndrome) in 15 men and 2 women with venous thromboembolism (VTE) or osteonecrosis 7 months (median) after starting testosterone therapy (TT), gel (30-50 mg/d), intramuscular (100-400 mg/wk), or HCG (6000 IU/wk).

Thrombophilia was studied in 2 healthy control groups without thrombosis (97 normal controls, 31 subjects on TT) and in a third control group (n = 22) with VTE, not on TT.

Of the 17 cases, 76% had >/=1 thrombophilia vs 19% of 97 normal controls (P < 0.0001), vs 29% of 31 TT controls (P = 0.002).

Cases differed from normal controls by Factor V Leiden (12% vs 0%, P = 0.021), by high Factor VIII (>150%) (24% vs 7%, P = 0.058), by high homocysteine (29% vs 5%, P = 0.007), and from both normal and TT controls for APL syndrome (18% vs 2%, P = 0.023, vs 0%, P = 0.04).

Despite adequate anticoagulation with TT continued after the first deep venous thrombosis-pulmonary embolus (DVT-PE), 1 man sustained 3 DVT-PEs 5, 8, and 11 months later and a second man had 2 DVT-PEs 1 and 2 months later.

Of the 10 cases with serum T measured on TT, 6 (60%) had supranormal T (>800 ng/dL) and of 9 with estradiol measured on TT, 7 (78%) had supranormal levels (>42.6 pg/mL).

TT interacts with thrombophilia leading to thrombosis. TT continuation in thrombophilic men is contraindicated because of recurrent thrombi despite anticoagulation.

Screening for thrombophilia before starting TT should identify subjects at high risk for VTE with an adverse risk/benefit ratio for TT.
 
Freedman J, Glueck CJ, Prince M, Riaz R, Wang P. Testosterone, thrombophilia, thrombosis. Transl Res. https://www.sciencedirect.com/science/article/pii/S1931524414004678

We screened previously undiagnosed thrombophilia (V Leiden-prothrombin mutations, Factors VIII and XI, homocysteine, and antiphospholipid antibody [APL] syndrome) in 15 men and 2 women with venous thromboembolism (VTE) or osteonecrosis 7 months (median) after starting testosterone therapy (TT), gel (30-50 mg/d), intramuscular (100-400 mg/wk), or HCG (6000 IU/wk).

Thrombophilia was studied in 2 healthy control groups without thrombosis (97 normal controls, 31 subjects on TT) and in a third control group (n = 22) with VTE, not on TT.

Of the 17 cases, 76% had >/=1 thrombophilia vs 19% of 97 normal controls (P < 0.0001), vs 29% of 31 TT controls (P = 0.002).

Cases differed from normal controls by Factor V Leiden (12% vs 0%, P = 0.021), by high Factor VIII (>150%) (24% vs 7%, P = 0.058), by high homocysteine (29% vs 5%, P = 0.007), and from both normal and TT controls for APL syndrome (18% vs 2%, P = 0.023, vs 0%, P = 0.04).

Despite adequate anticoagulation with TT continued after the first deep venous thrombosis-pulmonary embolus (DVT-PE), 1 man sustained 3 DVT-PEs 5, 8, and 11 months later and a second man had 2 DVT-PEs 1 and 2 months later.

Of the 10 cases with serum T measured on TT, 6 (60%) had supranormal T (>800 ng/dL) and of 9 with estradiol measured on TT, 7 (78%) had supranormal levels (>42.6 pg/mL).

TT interacts with thrombophilia leading to thrombosis. TT continuation in thrombophilic men is contraindicated because of recurrent thrombi despite anticoagulation.

Screening for thrombophilia before starting TT should identify subjects at high risk for VTE with an adverse risk/benefit ratio for TT.
You rang?[emoji12]
 
Walsh TJ, Shores MM, Fox AE, Moore KP, Forsberg CW, et al. Recent trends in testosterone testing, low testosterone levels, and testosterone treatment among Veterans. Andrology. http://onlinelibrary.wiley.com/doi/10.1111/andr.12014/abstract

Low serum testosterone (T) is common and increasingly prevalent with increased age. Recent studies report an ‘epidemic’ of T prescribing and concern about unnecessary T treatment.

We investigated the number of men tested for T, the prevalence of low serum T levels, and initiation of T treatment among those with low T levels in men treated at Veterans Affairs (VA) facilities in the Northwest US (VISN 20).

We identified male Veterans aged 40–89 years and examined yearly proportions of men tested for T, found to have low T levels (total T < 280 ng/dL, free T < 34 pg/mL, or bioavailable T < 84 ng/dL), and subsequently treated with T from 2002 to 2011. We excluded men who had T treatment in the year prior and men with diagnoses of prostate or breast cancer.

Treatment initiation was defined as the first prescription for T within a year following a low T test.

From 2002 to 2011, the yearly population of eligible men in VISN 20 increased from 129 247 to 163 572. The proportion of men who had serum T tests increased from 3.2% in 2002 to 5.8% in 2011. Among the tested men, the percentage of men with low T levels increased from 35.0 to 47.3%.

However, the proportion of men with low T levels who were given T treatment within a year decreased from 31.0 to 28.0%.

Despite large increases in T testing, and detection of men with low T levels, there was a slight decrease in the proportion of men with low T levels who were treated with T.

The decrease in T treatment during this time period contrasts with other studies and may be related to higher comorbidity in Veterans and/or VA formulary restrictions on the use of transdermal T formulations.


 
Tanna MS, Schwartzbard A, Berger JS, Alukal J, Weintraub H. The Role of Testosterone Therapy in Cardiovascular Mortality: Culprit or Innocent Bystander? Curr Atheroscler Rep. 2015;17(3):490. http://link.springer.com/article/10.1007/s11883-015-0490-0

Testosterone therapy is recommended for men with symptomatic androgen deficiency and unequivocally low testosterone levels. Although the prevalence of hypogonadism seems relatively constant, studies of prescribing patterns in both the United States and the United Kingdom show a dramatic increase in testosterone prescription in recent years, possibly due to increased marketing and inappropriate therapy. Concurrent with this, there has been growing concern regarding the potential adverse effects of testosterone therapy, particularly its cardiovascular risks.

In this review, we present our current understanding of the implications of testosterone deficiency, as well as the conflicting evidence surrounding the cardiovascular effects of testosterone replacement therapy.

Although there is a lack of adequate data, based on the current evidence, WE CONCLUDE THAT TESTOSTERONE THERAPY CAN BE SAFELY CONSIDERED IN MEN WITH APPROPRIATELY DIAGNOSED CLINICAL ANDROGEN DEFICIENCY AND INCREASED CARDIOVASCULAR RISK after a thorough discussion of potential risks and with guideline recommended safety monitoring.
 
Rochira V, Diazzi C, Santi D, Brigante G, Ansaloni A, et al. Low testosterone is associated with poor health status in men with human immunodeficiency virus infection: a retrospective study. Andrology. http://onlinelibrary.wiley.com/doi/10.1111/andr.310/abstract

Men with human immunodeficiency virus (HIV) infection are often hypogonadal and develop several HIV-associated non-acquired immunodeficiency syndrome (AIDS) (HANA) conditions that impair overall health status.

No studies explored the relationship between health status and serum testosterone (T) in HIV-infected men.

This study aims to investigate the association between total serum T and HANA, multimorbidity, and frailty in a large cohort of 1359 HIV-infected men and to explore the relationship between patients’ overall health status and serum T.

Among biochemical and hormonal measurement performed the main are serum total T, free triiodothyronine (fT3), and luteinizing hormone.

Other outcome measurements include anthropometry, assessment of comorbidities and disabilities, overall health status defined as the number of HANA and by the 38-item multimorbidity frailty index, anthropometry, and bone mineral density.

The cumulative relative risk of comorbidities is increased in HIV-infected men with hypogonadism (p < 0.001) and hypogonadism is associated with several comorbidities.

The prevalence of hypogonadism increases progressively with the increase of the number of comorbidities.

Frailty index is inversely related to serum total T (age-adjusted r = 0.298, r2 = 0.089, p < 0.0001).

Serum fT3 levels are significantly lower in hypogonadal than eugonadal men (p = 0.022).

This suggests that low serum T could be considered a sensitive marker of frailty and poor health status and that the latter might induce hypogonadism. The more HIV-infected men are frail the more they are hypogonadal.

This suggests that hypogonadism might be a naturally occurring condition in unhealthy HIV-infected men and raises concern about the safety of T treatment.

In conclusion, low serum T is associated with multimorbidity, HANA, and frailty in HIV-infected men and this association seems to be bidirectional.


Given the wide attitude to offer T treatment to HIV-infected men, caution is needed when prescribing T to HIV-infected male patients, especially if the patient is unhealthy or frail.
 
Seems like odd reasoning... how are they excluding a causal relationship between hypogonadism and frailty/poor health?

More precisely, what causes them to conclude that frailty causes hypogonadism and not the other way around?
 
Suppressive Effects Of Androgens On The Immune System

Highlights
· Androgens are protective in autoimmunity but promote cancer.
· Androgens suppress antibody response to vaccination and infection.
· Androgens suppress inflammatory immune cells like dendritic cells and macrophages.
· Androgens promote regulatory immune cells like MDSCs and Tregs.
· Development and function of T and B cells is dampened by androgens.

Trigunaite A, Dimo J, Jorgensen TN. Suppressive effects of androgens on the immune system. Cell Immunol. https://www.sciencedirect.com/science/article/pii/S0008874915000313

Sex-based disparities in immune responses are well known phenomena. The two most important factors accounting for the sex-bias in immunity are genetics and sex hormones.

Effects of female sex hormones, estrogen and progesterone are well established, however the role of testosterone is not completely understood.

Evidence from unrelated studies points to an immunosuppressive role of testosterone on different components of the immune system, but the underlying molecular mechanisms remains unknown.

In this review we evaluate the effect of testosterone on key cellular components of innate and adaptive immunity.

Specifically, we highlight the importance of testosterone in down-regulating the systemic immune response by cell type specific effects in the context of immunological disorders.

Further studies are required to elucidate the molecular mechanisms of testosterone-induced immunosuppression, leading the way to the identification of novel therapeutic targets for immune disorders.
 
Al-Khazaali A, Arora R, Muttar S. Controversial Effects of Exogenous Testosterone on Cardiovascular Diseases. Am J Ther. http://journals.lww.com/americanthe...fects_of_Exogenous_Testosterone_on.99135.aspx

The use of testosterone (T) among men aged 40 years or older was increased more than 3 times from 0.81% in 2001 to 2.91% in 2011. Until recently, the majority of the studies did not show any increased cardiovascular (CV) risk by using T in male patients with hypogonadism. What is more, some studies had observed a protective effect of using T against CV diseases.

However, in 2010, a randomized clinical trial (RCT) was intended to study the advantage of T gel in older men with limitations in mobility; the study was stopped due to unexpected high prevalence of CV adverse outcome. These findings were confirmed by 2 other studies published in November of 2013 and January of 2014.

Consequently, the Food and Drug Administration (FDA) had announced in January 2014 that it will reassess the safety of those treatments. Meanwhile, the agency had not reached to a definitive conclusion that FDA-approved testosterone therapy raises the risk of stroke, heart attack, or death.

A report released in the broadcast of the NBC Nightly News in September of this year that the FDA says "there's little evidence that T boosting drugs taken by millions of American men are actually effective." NBC notes that the agency also pointed out that it was not convinced that they carry serious risk either. "The condition has been marketed as low 'T', and the medications are offered to help with low sex drive and fatigue among some men," notes NBC.

The European Medicines Agency EMA's Pharmacovigilance Risk Assessment Committee has also responded to the concern of potential CV adverse outcomes associated with the use of T, and they have concluded in their October meeting of this year that the use of T in men who do not produce enough T raises the risk of heart diseases.

In our review, we highlighted the association between exogenous T and major adverse CV outcomes. Additionally, we focused on the interplay between exogenous T and some endocrine abnormalities such as diabetes mellitus type 2, metabolic syndrome, dyslipidemia, and obesity.
 
Baillargeon J, Urban RJ, Kuo YF, Holmes HM, Raji MA, et al. Screening and monitoring in men prescribed testosterone therapy in the U.S., 2001-2010. Public Health Rep. 2015;130(2):143-52. http://www.ncbi.nlm.nih.gov/pubmed/25729103

OBJECTIVES: The Endocrine Society recommends testosterone therapy only in men with low serum testosterone levels, consistent symptoms of hypogonadism, and no signs of prostate cancer. We assessed screening and monitoring patterns in men receiving testosterone therapy in the U.S.

METHODS: We conducted a retrospective cohort study of 61,474 men aged >/=40 years, and with data available in one of the nation's largest commercial insurance databases, who received at least one prescription for testosterone therapy from 2001 to 2010.

RESULTS: In the 12 months before initiating treatment, 73.4% of male testosterone users received a serum testosterone test and 60.7% received a prostate-specific antigen (PSA) test. Among men who were tested, 19.5% did not meet Endocrine Society guidelines for low testosterone. In the 12 months after initiating treatment, 52.4% received a serum testosterone test and 43.3% received a PSA test. Multivariable analyses showed that those seen by either an endocrinologist or urologist were more likely to receive appropriate tests.

CONCLUSIONS: A substantial number of men prescribed testosterone therapy did not receive testosterone or PSA testing before or after initiating treatment. In addition, almost one out of five treated men had baseline serum testosterone values above the threshold defined as normal by the Endocrine Society. Men treated by endocrinologists and urologists were more likely to have been treated according to guideline recommendations than men treated by other specialties, including primary care.
 
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FDA Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use.
http://www.fda.gov/Drugs/DrugSafety/ucm436259.htm


[This information is an update to the FDA Drug Safety Communication: FDA Evaluating Risk of Stroke, Heart Attack, and Death with FDA-Approved Testosterone Products issued on January 31, 2014. http://www.fda.gov/Drugs/DrugSafety/ucm383904.htm]

The U.S. Food and Drug Administration (FDA) cautions that prescription testosterone products are approved only for men who have low testosterone levels caused by certain medical conditions.

The benefit and safety of these medications have not been established for the treatment of low testosterone levels due to aging, even if a man’s symptoms seem related to low testosterone.

We are requiring that the manufacturers of all approved prescription testosterone products change their labeling to clarify the approved uses of these medications.

We are also requiring these manufacturers to add information to the labeling about a possible increased risk of heart attacks and strokes in patients taking testosterone.

Health care professionals should prescribe testosterone therapy only for men with low testosterone levels caused by certain medical conditions and confirmed by laboratory tests.
 
1126M-13 - Effects of Testosterone Supplement Therapy on Cardiovascular Outcomes in Men with Low Testosterone
http://www.abstractsonline.com/pp8/#!/3658/presentation/35368

Background: Cardiovascular (CV) effects of testosterone supplement therapy in men with low testosterone levels have been inconsistently documented across studies.

Methods: Data for men with low total testosterone levels (<300 ng/dL) during 2007-13 were obtained from a large community-based healthcare system.

Cox proportional hazards (CPH) models were developed to examine effects of testosterone therapy on CV outcomes (acute myocardial infarction [AMI], stroke or death).

Single- and multi-variable models and stepwise-variable selection procedures provided estimates of unadjusted and adjusted hazard ratios (HR) and identified best predictors of outcome.

Adjusted effects of testosterone supplement were also examined in a subset of patients 1:1 propensity-matched (caliper=0.10) by several variables.

Results: A total of 7,245 men were identified, with a mean age of 54 yrs and mean follow-up period of 1.78 yrs (SD=0.86). Dyslipidemia was present in 41%, hypertension in 34%, current or prior smoking in 25%, diabetes mellitus in 17% and chronic kidney disease in 3.4%.

The combined event rate of AMI, stroke and death at 3 years was low in the treated (5.5%) and untreated (6.7%) groups. On single-variable CPH analysis, testosterone therapy appeared to be beneficial with reduced outcomes [unadjusted HR: 0.71 (0.51-0.98); p=0.038]. However, on multi-variable analysis, after adjusting for baseline differences, testosterone therapy was no longer significant (p=0.54).

Age, prior AMI and stroke/transient ischemic attack, dyslipidemia, smoking status and length of follow-up were independent predictors of the combined outcome.

Effects of testosterone supplement on CV outcomes were non-significant when adjusted through 1:1 matching in 3,115 matched-pairs [adjusted HR: 0.86 (0.57-1.29)] and the mean number of days to a CV event [1,044 (SE=4) vs. 955 (SE=3)] did not differ between treated and non-treated men (P=0.46).

Conclusions: CV event rates were low in men with low testosterone. While unadjusted analysis suggests CV benefits of testosterone replacement, men treated vs. not treated for low testosterone differ in CV risk factors and, when accounted for, differences in CV outcomes disappear.
 
1195-376 - Effect of Testosterone Therapy on Adverse Cardiovascular Events Among Men: A Meta-Analysis
http://www.abstractsonline.com/pp8/#!/3658/presentation/35861


Background: Testosterone therapy is widely used among men. Controversy persists regarding the effect of testosterone therapy on adverse cardiovascular events among men.

Two recent studies have shown an increased risk of adverse cardiovascular events with testosterone therapy in men.

We performed this meta-analysis to evaluate the effect of testosterone therapy on adverse cardiovascular events among men.

Methods: We performed a systematic literature search for studies evaluating effect of testosterone therapy versus no testosterone therapy on cardiovascular events among men. Studies providing data on the outcome of cardiovascular events were included.

Statistical heterogeneity across the various trials was tested using the Cochran’s Q statistic and I2 was computed to quantify heterogeneity. A two-sided alpha error of less than 0.05 was considered to be statistically significant (p < 0.05).

Results: Total of 29 eligible studies involving 122,889 men was included. The studies were heterogeneous; hence the random-effect model was used to calculate combined relative risk (RR).

Meta-analysis revealed that testosterone therapy does not cause statistically significant adverse cardiovascular events among men (RR, 1.168; CI, 0.794 to 1.718; p = 0.431).

Conclusion: Testosterone therapy may not be associated with adverse cardiovascular events among men. Future randomized controlled trials are necessary to characterize the effects of testosterone therapy on potential adverse cardiovascular events among men.
 
1140-124 - Effect of Testosterone Replacement Therapy on Incidence of Deep Vein Thrombosis and Pulmonary Embolism
http://www.abstractsonline.com/pp8/#!/3658/presentation/35257


Background: Testosterone Replacement Therapy (TRT) prescriptions have increased 400% in the last decade. Concern over the risk of deep venous thrombosis (DVT) and pulmonary embolism (PE) with TRT has led the FDA to issue an alert. The association of TRT with DVT/PE is not clearly understood.

The aim of this study was to examine the incidence of DVT/PE following TRT using a large patient database.

Methods: We used Veteran Affairs Informatics and Computing Infrastructure (VINCI) database, to select a cohort of US veterans who were found to have low serum total testosterone levels (sTT) during 1999 - 2012.

We compared the risk of incidence of DVT/PE between those who received TRT resulting in normalization of sTT and those who did not receive TRT. Those with prior history of DVT/PE were excluded.

The risk adjusted and unadjusted approaches were used to adjust for the potential confounding effects. We also assessed various independent risk factors and their association with DVT/PE risk.

Results: Of a total of 54000 patients with low sTT, 41121 received TRT (mean age = 63.9 yrs ± 11.4, mean follow-up = 5.9 yrs ± 3.2) while 12879 did not (mean age = 67.0 yrs ± 13.4, mean follow-up = 4.4 yrs ± 3.0).

New cases of DVT/PE were identified in 259 patients in the TRT group vs. 59 in the non-TRT group.

Table shows that there was no statistically significant increase in the incidence of DVT/PE following TRT therapy.

Conclusion: In patients with low sTT , TRT did not result in a statistically significant increase in incidence of DVT/PE.
 
Rosano GC, Vitale C, Fini M. Testosterone in men with hypogonadism and high cardiovascular risk, Pros. Endocrine. 2015;1-6. http://link.springer.com/article/10.1007/s12020-015-0561-6

Although numerous randomized studies have shown that testosterone replacement therapy (TRT) improves intermediate outcomes in patients at risk and in those with proven cardiovascular disease (CVD), results derived mainly from registries and observational studies have suggested an increased cardiovascular risk in elderly men receiving often supra-therapeutic doses of testosterone.

Recent meta-analyses have shown that when testosterone has been used in patients with pre-existing cardiovascular conditions, the effect on the disease has been either beneficial or neutral. Similar results have been reported in hypo- and eugonadal men.

Contrasting results have been reported by two trials of testosterone treatment in frail elderly men.

Reports from poorly analyzed databases have reported an increased risk of cardiovascular events with testosterone use.

More recently, a population-based study showed no increased cardiovascular risk of testosterone replacement in hypogonadal men.

Available data from controlled clinical trials suggest that the use of testosterone in elderly men does not increase cardiovascular risk nor the risk of events.

Studies in men with CVD, angina, or heart failure report a benefit from testosterone replacement in men with or without hypogonadism.

Therefore, at present, the cardiovascular benefits of TRT in elderly men outweigh the risks. This is particularly evident in those men with pre-existing CVD.
 
Effects of Androgens and Estrogens on Cardiometabolic Parameters in Young Adult Men
https://endo.confex.com/endo/2015endo/webprogram/Paper20646.html

Background: The higher prevalence of cardiovascular disease in men than in premenopausal women suggests that testosterone may promote and/or that estradiol may protect against CVD.

Existing studies of the roles of androgens vs estrogens on known CVD risk factors and other potentially–related metabolic factors have produced highly variable results.

Methods: We recruited 2 cohorts of healthy men aged 20-50. All men received goserelin acetate (Zoladex®, AstraZeneca LP, 3.6 mg q4wk) to suppress endogenous testosterone (T) and estradiol (E). Men in Cohort 1 (n=198) were randomized to receive a placebo gel or 1.25 g, 2.5 g, 5 g, or 10 g of testosterone gel (AndroGel®, Abbvie) daily for 16 weeks.

Men in Cohort 2 (n=202) received the same regimen plus all men received anastrozole (Arimidex®, AstraZeneca LP, 1 mg/d) to block conversion of T to E.

Fasting serum leptin, lipids, glucose, and HOMA-IR were measured every 4 weeks. Intramuscular (IM) fat was measured at the thigh by quantitative computed tomography at 0 and 16 weeks.

Changes were assessed between T dose groups within Cohort 2 to assess T effects, and between Cohorts 1 and 2 to assess E effects.

Results: By design, mean serum T levels ranged from prepubertal to high-normal and were similar in both cohorts (mean T=44, 191, 337, 470, and 805 ng/dL in Cohort 1 vs. 41, 231, 367, 485, and 924 ng/dL in Cohort 2 at T doses of 0, 1.25, 2.5, 5, and 10 gm of T/day; P=NS at each dose).

Mean serum E levels increased progressively with T dose escalation in Cohort 1 (3.6, 7.9, 11.9, 18.2, and 33.3 pg/mL) but remained <3 pg/mL in all dose groups in Cohort 2 (P<0.001 between cohorts).

Serum HDL and leptin levels were inversely associated with T dose in both cohorts (P<0.001 for all). This relationship was not altered by suppressing estrogen production, indicating that T alone regulates these measures.

In contrast, fasting glucose, HOMA-IR, and IM fat increased similarly in all men in Cohort 2 regardless of T dose group, and were significantly higher than in Cohort 1 (P<0.05 for all), indicating that E primarily regulates these measures.

Changes in blood pressure, LDL, and body weight were not significantly associated with T or E.

Conclusions: Whereas worsening of insulin resistance and accumulation of body fat due to low estrogen levels are consistent with the known male predominance in CVD, changes in LDL and blood pressure, the parameters most consistently related to cardiovascular risk, do not appear to be regulated by gonadal steroids.

Even though leptin is made by adipocytes, it’s circulating level is regulated exclusively by androgens in men.

These findings may contribute to a better understanding of the roles of androgens and estrogens in gender differences in CVD.
 
The Association Between Testosterone Use and Major Adverse Cardiovascular Events (MACE): An Exploratory Retrospective Cohort Analysis of Two Large, Contemporary, Coronary Heart Disease Clinical Trials
https://endo.confex.com/endo/2015endo/webprogram/Paper19549.html

Background: The cardiovascular (CV) safety profile of testosterone replacement therapy (TRT) in men is uncertain, particularly in older individuals with pre-existing coronary heart disease (CHD), and has been heightened by recent retrospective analyses of observational data.1

Prior studies, including relatively small prospective clinical trials of hypogonadal men, have yielded conflicting results. Additional data are required to address this safety concern.

Objectives and Methods: We utilized data from two large, international, double blind, placebo-controlled randomised clinical trials evaluating the potential effect of darapladib, a lipoprotein phospholipase A2 inhibitor, on ischemic events.

Subjects were men and women with documented stable coronary heart disease (N=15,828; STABILITY2) or recent acute coronary syndrome (N=13,026; SOLID3).

Cardiovascular risk factors were managed according to ‘standard of care’, and major adverse cardiovascular events (MACE - CV death, non-fatal MI, and non-fatal stroke) were prospectively ascertained and adjudicated.

These trials were recently completed and had median follow-up periods of 3.7 and 2.5 years, respectively. Darapladib did not significantly reduce the risk of CV events.

Cox proportional hazards modelling was used to assess the risk of MACE in men who were exposed to testosterone (< 12 months and > 12 months) compared to those not exposed to testosterone using data from both trials combined.

The models were adjusted for treatment group, age, BMI, HDL/Total cholesterol ratio, Systolic BP, GFR, diabetes, aspirin use, statin use and smoking status.

Results: TRT use amongst male trial subjects was low (N=217, 1%) and most (83%) was by US men. The majority of MACE events (N=1412, 57%) were myocardial infarctions.

Men exposed to TRT for less than or equal to 12 months had a hazard ratio of 0.48 (95% CI: (0.15, 1.49), p=0.21) compared to those not exposed to TRT. Men exposed to TRT for greater than 12 months had a hazard ratio of 0.47 (95% CI: (0.25, 0.87), p=0.02) compared to those not exposed to TRT.

Conclusions: Pooled analyses of both studies, including adjustment for potential confounders, suggest that TRT is not associated with an increased risk of MACE in men with well characterised coronary heart disease.

Despite the limitations of this retrospective analysis, including small numbers of TRT exposed men and lack of ascertainment of gonadal status, these data do not corroborate recent observational reports that testosterone therapy is associated with increased CV risk.

(1) The Risk of Cardiovascular Events in Men Receiving Testosterone Therapy. An Endocrine Society Statement. Feb. 7 2014.
(2) Darapladib for Preventing Ischemic Events in Stable Coronary Heart Disease. NEJM 2014; 370: 1702.
(3) Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. JAMA. doi:10.1001/jama.2014.11061
 
Dohle GR. Words of wisdom: re: long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Eur Urol. 2014;66(5):965-6. http://www.europeanurology.com/article/S0302-2838(14)00781-7/fulltext/re-long-term-testosterone-therapy-in-hypogonadal-men-ameliorates-elements-of-the-metabolic-syndrome-an-observational-long-term-registry-study

Traish AM, Haider A, Doros G, Saad F. Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int J Clin Pract. http://onlinelibrary.wiley.com/doi/10.1111/ijcp.12319/full

Expert's summary:

In a follow-up study of 255 hypogonadal men on testosterone supplementation therapy (TST), the authors evaluated changes in signs and symptoms of the metabolic syndrome. All men received testosterone undecanoate 1000-mg injections at 3-mo intervals for a period of 60 mo. Anthropometric measurements (body weight, waist circumference, prostate volume, blood pressure) were performed at follow-up visits, along with laboratory examinations (lipids, glucose, liver enzymes and haemoglobin A1c, prostate-specific antigen [PSA]).

The authors found a marked and sustainable reduction in body weight, waist circumference, and blood pressure throughout the study period and improvement of the lipid profile and blood glucose. Prostate volume and PSA slightly increased with TST but without prostate-related symptoms.

Three patients were diagnosed with prostate cancer during the study; this number was much lower than expected.

This study confirms that TST can help improve symptoms of the metabolic syndrome, including weight reduction and improved hypertension and diabetes regulation.

Expert's comments:

The metabolic syndrome is characterised by overweight status, hypertension, insulin resistance, type 2 diabetes mellitus, hypercholesterolemia, and an increased risk of cardiovascular disease (CVD). Men with obesity often have testosterone deficiency due to the activity of the enzyme aromatase, which is abundantly present in fatty tissue. Aromatase converts testosterone in estradiol [1].

Hypogonadism is associated with an increased risk of all-cause and CVD mortality [2]. This long-term follow-up study confirms the positive results of TST on diabetes control and lipid profile, which will result in a lower risk for cardiovascular incidents in these patients [3]. This finding needs to be confirmed in prospective controlled trials, such as the ongoing European Male Ageing Study (EMAS) [4].

These findings are of importance to urologists because we often see these patients first in our practice for sexual problems. Sexual symptoms together with low testosterone appeared to be strong and independent risk factors for a high risk of cardiovascular incidents and death in these patients [4]. Urologists are sometimes reluctant to start TST due to unfamiliarity with reproductive endocrinology and potential serious side effects of TST, such as cardiovascular events and newly diagnosed prostate cancer. Based on recent publications, however, there is growing evidence that TST has clear advantages in well-selected patients in terms of improving symptoms and health outcomes in hypogonadal men without increasing the risk of prostate cancer and cardiovascular mortality. Testosterone supplementation is clearly contraindicated in men with advanced prostate cancer and uncontrolled CVD [1], but many other symptomatic hypogonadal men may benefit from hormonal substitution.

Low testosterone appears to be a marker for poor health status, and substitution therapy together with an improvement in lifestyle can reverse certain risks associated with obesity and diabetes. Weight reduction and exercise remain the primary goals for the patients, but TST seems to help improve disease control. Close follow-up of patients under TST is mandatory, with a special focus on polycythaemia (elevated haematocrit), which can occur in some of these men under therapy and may increase the risk for thrombosis. The treatment of hypogonadal men is a multidisciplinary process, and urologists need to have both the knowledge and the skills to diagnose and manage hypogonadal men who may benefit from TST.

References

[1] Dohle GR, Arver S, Bettocchi C, Kliesch S, Punab M, de Ronde W. Guidelines on male hypogonadism. European Association of Urology Web site. http://uroweb.org/wp-content/uploads/16-Male-Hypogonadism_LR.pdf

[2] M.M. Shores, N.L. Smith, C.W. Forsberg, B.D. Anawalt, A.M. Matsumoto. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab. 2012;97:2050-2058. http://press.endocrine.org/doi/abs/10.1210/jc.2011-2591

[3] V. Muraleedharan, H. Marsh, D. Kapoor, K.S. Channer, T.H. Jones. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol. 2013;169:725-733. http://www.eje-online.org/content/169/6/725

[4] S.R. Pye, I.T. Huhtaniemi, J.D. Finn, et al., EMAS Study Group. Late-onset hypogonadism and mortality in aging men. J Clin Endocrinol Metab. 2014;99:1357-1366. http://press.endocrine.org/doi/abs/10.1210/jc.2013-2052
 
1126M-13 - Effects of Testosterone Supplement Therapy on Cardiovascular Outcomes in Men with Low Testosterone
http://www.abstractsonline.com/pp8/#!/3658/presentation/35368

Background: Cardiovascular (CV) effects of testosterone supplement therapy in men with low testosterone levels have been inconsistently documented across studies.

Methods: Data for men with low total testosterone levels (<300 ng/dL) during 2007-13 were obtained from a large community-based healthcare system.

Cox proportional hazards (CPH) models were developed to examine effects of testosterone therapy on CV outcomes (acute myocardial infarction [AMI], stroke or death). Single- and multi-variable models and stepwise-variable selection procedures provided estimates of unadjusted and adjusted hazard ratios (HR) and identified best predictors of outcome.

Adjusted effects of testosterone supplement were also examined in a subset of patients 1:1 propensity-matched (caliper=0.10) by several variables.

Results: A total of 7,245 men were identified, with a mean age of 54 yrs and mean follow-up period of 1.78 yrs (SD=0.86).

Dyslipidemia was present in 41%, hypertension in 34%, current or prior smoking in 25%, diabetes mellitus in 17% and chronic kidney disease in 3.4%. The combined event rate of AMI, stroke and death at 3 years was low in the treated (5.5%) and untreated (6.7%) groups.

On single-variable CPH analysis, testosterone therapy appeared to be beneficial with reduced outcomes [unadjusted HR: 0.71 (0.51-0.98); p=0.038]. However, on multi-variable analysis, after adjusting for baseline differences, testosterone therapy was no longer significant (p=0.54).

Age, prior AMI and stroke/transient ischemic attack, dyslipidemia, smoking status and length of follow-up were independent predictors of the combined outcome.

Effects of testosterone supplement on CV outcomes were non-significant when adjusted through 1:1 matching in 3,115 matched-pairs [adjusted HR: 0.86 (0.57-1.29)] and the mean number of days to a CV event [1,044 (SE=4) vs. 955 (SE=3)] did not differ between treated and non-treated men (P=0.46).

Conclusions: CV event rates were low in men with low testosterone. While unadjusted analysis suggests CV benefits of testosterone replacement, men treated vs. not treated for low testosterone differ in CV risk factors and, when accounted for, differences in CV outcomes disappear.
 
1195-376 - Effect of Testosterone Therapy on Adverse Cardiovascular Events Among Men: A Meta-Analysis
http://www.abstractsonline.com/pp8/#!/3658/presentation/35861

Background: Testosterone therapy is widely used among men. Controversy persists regarding the effect of testosterone therapy on adverse cardiovascular events among men. Two recent studies have shown an increased risk of adverse cardiovascular events with testosterone therapy in men. We performed this meta-analysis to evaluate the effect of testosterone therapy on adverse cardiovascular events among men.

Methods: We performed a systematic literature search for studies evaluating effect of testosterone therapy versus no testosterone therapy on cardiovascular events among men. Studies providing data on the outcome of cardiovascular events were included.

Statistical heterogeneity across the various trials was tested using the Cochran’s Q statistic and I2 was computed to quantify heterogeneity. A two-sided alpha error of less than 0.05 was considered to be statistically significant (p < 0.05).

Results: Total of 29 eligible studies involving 122,889 men was included. The studies were heterogeneous; hence the random-effect model was used to calculate combined relative risk (RR). Meta-analysis revealed that testosterone therapy does not cause statistically significant adverse cardiovascular events among men (RR, 1.168; CI, 0.794 to 1.718; p = 0.431).

Conclusion: Testosterone therapy may not be associated with adverse cardiovascular events among men. Future randomized controlled trials are necessary to characterize the effects of testosterone therapy on potential adverse cardiovascular events among men.
 
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