Androgen Replacement

Discussion in 'Men's Health Forum' started by Michael Scally MD, Sep 30, 2010.

  1. foreveryoung

    foreveryoung Member

    on the forums is almost getting so bad you see 25 year olds with near mid range test levels calling it low T and complaining that there were others better at sports and with more muscles than them no matter how hard they worked in gym therefore their low T was a problem... I can understand that their needs to be responsibility and that is a part of the controversy as well.. i don't think we want to live in a society where millions of 20 something year old guys are injecting a bunch of testosterone, it's been ok underground and amongst a subculture
  2. foreveryoung

    foreveryoung Member

    seeing more and more posts of the typical "treatment" the trt clinics are doping up their clients with and maybe something does need to be done. .. they aren't practicing medicine of normalcy anymore... seems common now for guys to say they are prescribed 200mg test a week and hcg and arimidex
    Millard Baker likes this.
  3. foreveryoung

    foreveryoung Member

    worse still... a lot of those guys come on here asking about "blasting" on top of these prescribed protocols.... the whole thing is getting out of control, there should be controversy
    Michael Scally MD likes this.
  4. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Dean J, Maggi M, de Boer BJ, Hellstrom W, Khera M, et al. Diagnosing secondary hypogonadism: important consequences for fertility and reversibility. BJU Int.

    Hypogonadism (HG, testicular failure in men) has become a controversial and much misunderstood condition.

    Many men perceive testosterone as a panacea for the ills of ageing and "Low-T clinics" have sprung up to meet their demands, even though testosterone is often not the answer.

    In light of the unprecedented rise in testosterone prescriptions in recent years, particularly amongst middle-aged men, the US Food and Drug Administration (FDA) issued a Safety Communication in May 2015 intended to restrict the use of testosterone.
    Millard Baker likes this.
  5. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    [Open Access] Goodman N, Guay A, Dandona P, Dhindsa S, Faiman C, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on the Association of testosterone and Cardiovascular Risk. Endocr Pract. 2015;21(9):1066-73.

    This document represents the official position of the American Association of Clinical Endocrinologists and the American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician.

    ABBREVIATIONS: CI = confidence interval FDA = Food and Drug Administration LH = luteinizing hormone MI = myocardial infarction TRT = testosterone replacement therapy.


    Several recent publications have raised concern that testosterone replacement therapy (TRT) in men increases cardiovascular risk (1,2). This resulted in the U.S. Food and Drug Administration (FDA) holding a hearing and issuing the following statement on March 3, 2015:

    “Health care professionals should prescribe testosterone therapy only for men with low testosterone levels caused by certain medical conditions and confirmed by laboratory tests. Health care professionals should make patients aware of the possible increased cardiovascular risk when deciding whether to start or continue a patient on testosterone therapy. Patients using testosterone should seek medical attention immediately if symptoms of a heart attack or stroke are present, such as chest pain, shortness of breath or trouble breathing, weakness in one part or one side of the body, or slurred speech. Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program.”

    It is the purpose of this document to state briefly the position of American Association of Clinical Endocrinologists on the association of TRT with cardiovascular risk. A detailed document presenting the scientific evidence for the association of low testosterone concentrations with and the effects of testosterone therapy upon cardiovascular risk follows this statement.

    The key points described in the document are:

    Epidemiologic studies strongly support the association of low testosterone concentrations and hypogonadism with cardiovascular events and all-cause mortality, especially in elderly men (3,4). However, low testosterone could be a marker of illness and not a causal factor.

    TRT favorably changes many cardiovascular risk factors. It decreases fat mass, increases muscle mass, decreases insulin resistance and can reverse metabolic syndrome in some men (5).

    Randomized controlled trials have not been powered to evaluate the effect of testosterone replacement in men on cardiovascular events or mortality. However, 2 retrospective reports have raised concern that testosterone therapy increases cardiovascular risk (1,2). As reviewed in the accompanying document and in the March 3, 2015 FDA report (available online at:, these studies have major flaws precluding meaningful conclusions to be drawn. A more recent retrospective cohort study using enrollment and claims data for Medicare beneficiaries showed no effect of TRT on myocardial infarctions (6). However, this study suffered from the same limitations as those mentioned above.

    Following a formal in-depth review, the FDA released a new warning and updated labeling on TRT to reflect the possible increased risk of heart attacks and strokes associated with testosterone use. The Committee concurs in the FDA conclusion that the signal for cardiovascular risk is weak and that we need definitive studies.

    The FDA also recommended that: “Testosterone is an FDA-approved replacement therapy only for men with disorders of the testicles, pituitary gland or brain that cause hypogonadism” and that “it should not be used to relieve symptoms in men who have low testosterone for no reasons other than aging.”

    This recommendation is not clear. It is our opinion that any patient being considered for TRT must undergo a thorough diagnostic work-up (7–9). The decision to replace testosterone should be guided by the signs/symptoms and testosterone concentrations rather than the underlying cause. These men should be told that we do not have definitive studies demonstrating efficacy or risk for treating men with these conditions. The committee agrees that the risk/benefit ratio of TRT is not well established in aging-associated hypogonadism. Our recommendations follow:

    a) We recommend that symptomatic men who have unequivocally low total and/or free testosterone levels that are assayed on at least 2 samples drawn before 10 am should be considered for TRT.

    b) We advise the practicing clinician to be extra cautious in the symptomatic elderly with demonstrably low testosterone levels prior to embarking on replacement therapy and to avoid treatment of the frail elderly until better outcome data are available.

    Conclusion: Recent reports related testosterone treatment to increased cardiovascular events. However, there is no compelling evidence that testosterone therapy either increases or decreases cardiovascular risk. Large-scale prospective randomized controlled trials on testosterone therapy, focusing on cardiovascular benefits and risks, are clearly needed. As with therapeutics in general, common sense, experience, and an individualized approach are recommended.
    Millard Baker and Burrr like this.
  6. Burrr

    Burrr Member Supporter

    The test dosage may be a little high, but is it really all that dangerous in an otherwise healthy man? Whats the problem with adex and HCG?
    tenpoundsleft likes this.
  7. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Handelsman DJ, Yeap B, Flicker L, Martin S, Wittert GA, et al. Age-specific population centiles for androgen status in Australian men. European Journal of Endocrinology.

    Context: The age-specific population profiles in men of circulating testosterone (T) and its two bioactive metabolites dihydrotestosterone (DHT) and estradiol (E2) across the adult lifespan and its determinants are not well described.

    Objective: To deduce smoothed age-specific centiles of circulating testosterone T, DHT and E2 in men using pooled data from population-based studies in 3 Australian cities from liquid chromatography-mass spectrometry (LC-MS) steroid measurements in a single laboratory.

    Design, Setting and Participants: Pooled data of 10,904 serum samples (serum T, DHT, E2, age, height, weight) from observational population-based studies in 3 major cities across Australia.

    Main Outcome Measures: Age-specific smoothed centiles for serum T, DHT and E2 in men aged 35 to 100 years deduced by large sample data analysis methods.

    Results: Serum T, DHT and E2 decline gradually from ages 35 onwards with a more marked decline after 80 years of age. Higher weight, body mass index (BMI) and body surface area (BSA) as well as shorter stature are associated with reduced serum T, DHT and E2.

    Conclusions: Among Australian men, there is gradual progressive population-wide decline in androgen status during male ageing until the age of 80 years after which there is a more marked decline. Obesity and short stature are associated with reduced androgen status.

    Research into the age-related decline in androgen status should focus on the progressive accumulation of age-related comorbidities to better inform optimal clinical trial design.
  8. tenpoundsleft

    tenpoundsleft Member

    Sounds like a bunch of BS - first they say "TRT favorably changes many cardiovascular risk factors. It decreases fat mass, increases muscle mass, decreases insulin resistance and can reverse metabolic syndrome in some men" and then they say "it should not be used to relieve symptoms in men who have low testosterone for no reasons other than aging" - WTF!!!!!

    All things in moderation - take an aspirin or two a day - and it's great - take the whole bottle and you might die. FFS, can't they practice their medicine along a grey scale? This is as bad as our boys in blue and their obsession with speed limits - which have precious little to do with safety on the roads. Everybody looking for easy black/white triggers so we can prescribe/proscribe without thinking. Arrrrrrgh.
    korat likes this.
  9. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Handelsman DJ, Sikaris K, Ly LP. ANNALS EXPRESS: Estimating Age-Specific Trends in Circulating testosterone and SHBG in Males and Females Across the Lifespan. Ann Clin Biochem.

    BACKGROUND: Age-specific trends of serum testosterone (T) and sex hormone binding globulin (SHBG) across the full lifespan have not been reported.

    METHODS: We deduced age-specific trends in serum testosterone and SHBG in males and females between ages 10 and 90 from a large sample of consecutive results from a single large pathology laboratory.

    Coded results of 110,712 consecutive blood samples requesting serum testosterone over 7 years (2007-13) comprising blood T, SHBG and calculated free T (cFT) together with gender and age were analyzed create smoothed age-specific centiles (2.5%, 5%, 25%, 50%, 75%, 95%, 97.5%) for males and females.

    RESULTS: These identified the pubertal increases in serum T in males peaking at 20 years of age and remaining stable thereafter until the 8t h decade.

    In women circulating T peaked in late adolescence and declined gradually over the next 2 decades but remained stable across menopause and beyond.

    After early childhood, serum SHBG declines to a nadir in men the age of 20 years and remain stable till the 6t h decade with a gradual, progressive rise thereafter.

    In women the SHBG nadir is reached earlier with levels rising gradually and progressively with age thereafter and accelerating after the age of 70 years. Women also exhibit a second SHBG peak during reproductive ages reflected only in upper centiles due to effects of pregnancy and oral contraceptive use in a significant minority of women.

    CONCLUSIONS: This large sample of clinical data provides a comprehensive profile of androgen status across the lifespan from early adolescence to late old age.
  10. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    testosterone courses downplay risks, lead to overuse in older men.

    The testosterone courses are at the forefront of a resurgence in industry-funded continuing medical education courses, often offered for free to doctors who need the credits to maintain their medical licenses, a Milwaukee Journal Sentinel/MedPage Today investigation found.

    The funding dropped temporarily after congressional investigations showed drug companies had manipulated such programs to market unapproved uses for their products. But income for the courses rebounded to a near-record $2.7 billion last year.

    Of that, $676 million, or about a quarter, came from the drug and medical device industry.

    With many universities turning their backs on the funding, and new federal requirements to disclose payments made directly to doctors, drug companies found a way to elude transparency reforms and continue to influence the courses:

    Payments increasingly are made to third-party organizations — often for-profit firms — that help create the materials, hire the faculty and put on the courses. Those payments don't have to be disclosed.

    Consider it the dark money of medicine.
    Millard Baker likes this.
  11. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Re: testosterone Lab Testing and Initiation in the United Kingdom and the United States, 2000 to 2011

    Scovell JM, Ramasamy R, Lipshultz LI. Re: Testosterone Lab Testing and Initiation in the United Kingdom and the United States, 2000 to 2011. European Urology 2015;66(4):786-7.

    Layton JB, Li D, Meier CR, et al. Testosterone Lab Testing and Initiation in the United Kingdom and the United States, 2000 to 2011. J Clin Endocrinol Metab 2014;99:835–42.

    Experts’ summary:

    The retrospective cohort study by Layton and colleagues sought to describe the patterns of testosterone testing and testosterone prescriptions in men in the United Kingdom and the United States. The authors utilized data from general practitioner health care records in the United Kingdom and from both commercial and Medicare insurance claims in the United States between 2000 and 2011. This study found that testosterone testing rates increased in both countries and that new testing in untreated patients rose threefold in the United Kingdom and more than fourfold in the United States.

    This study observed that a significant proportion of men in their reproductive years received testosterone supplementation. Men aged 18–39 yr accounted for a significant minority of new testosterone prescriptions (United Kingdom: 16%; United States: 12%), and a higher proportion of US men with normal or high serum testosterone levels received testosterone prescriptions (United Kingdom: 1%; United States: 4–9%).

    This discrepancy in testing and diagnosis was also evident from the fact that in the United Kingdom, 88% of men who were prescribed testosterone were diagnosed with clinical or laboratory hypogonadism compared with only 60% of men in the United States.

    Experts’ comments:

    The study by Layton et al., using data from both UK and US cohorts, highlights the discrepancies between a definitive diagnosis of hypogonadism and interventional treatment. This study, along with an analysis performed by Baillargeon and colleagues [1], provides evidence for what we already see in clinical practice, namely, that the number of testosterone therapy prescriptions has risen dramatically over the past decade.

    Because practitioners have become more aware of hypogonadism, we would hope to see an increase in laboratory testing but with a smaller increase in testosterone therapy.

    These data, however, demonstrate an alarming trend.

    A subset of patients are not receiving adequate testing [2] prior to initiation of testosterone therapy, and more men are being prescribed testosterone therapy despite no clinical or laboratory diagnosis of hypogonadism.

    This study provides clear evidence that guidelines for testosterone therapy initiation are seldom followed, and in the United States, the lack of adherence to guidelines has led to an overabundance of potentially unnecessary testosterone prescriptions.

    Another alarming trend highlighted in the study is that in both countries, >10% of men initiating testosterone therapy are within their reproductive years. Practitioners often, do not consider the inhibitory effect of exogenous testosterone on a male's reproductive potential. In fact, a 2010 survey of American Urological Association members found that up to 25% of urologists would prescribe testosterone therapy for idiopathic male infertility [3], suggesting that the impact on fertility often is not only ignored but also incorrectly understood.

    A survey of Canadian men presenting at a male infertility clinic between 2008 and 2012 found that an alarming 39% of the men on testosterone therapy received the prescription from either an endocrinologist or a urologist [4]. This finding suggests that a large group of men desiring fertility are receiving testosterone supplementation from practitioners outside the fields of endocrinology or urology and that some endocrinologists or urologists are not appropriately considering the ramifications of exogenous testosterone on fertility.

    The reported discrepancy between adequate testing and new testosterone prescriptions highlights the need for increased physician education and the proper management of these patients by practitioners trained in appropriately diagnosing and treating male hypogonadism.


    [1] J. Baillargeon, R.J. Urban, K.J. Ottenbacher, K.S. Pierson, J.S. Goodwin. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med, 173 (2013), pp. 1465–1466.

    [2] S. Bhasin, G.R. Cunningham, F.J. Hayes, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 95 (2010), pp. 2536–2559.

    [3] E.Y. Ko, K. Siddiqi, R.E. Brannigan, E.S. Sabanegh Jr. Empirical medical therapy for idiopathic male infertility: a survey of the American Urological Association. J Urol, 187 (2012), pp. 973–978.

    [4] M.K. Samplaski, Y. Loai, K. Wong, K.C. Lo, E.D. Grober, K.A. Jarvi. Testosterone use in the male infertility population: prescribing patterns and effects on semen and hormonal parameters. Fertil Steril, 101 (2014), pp. 64–69.
    Millard Baker likes this.
  12. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Agergaard Holmboe S, Vradi E, Kold Jensen T, et al. The association of reproductive hormone levels and all-cause, cancer and cardiovascular disease mortality in men. The Journal of Clinical Endocrinology & Metabolism.

    Context: testosterone levels (T) have been associated with mortality, but controversy exists.

    Objective: To investigate associations between serum levels of total testosterone, SHBG, free testosterone, estradiol, LH and FSH, and subsequent mortality with up to 30 years of follow-up.

    Design: A prospective cohort study consisting of men participating in four independent population-based surveys (MONICA I-III and Inter99) from 1982 to 2001 and followed until December 2012 with complete registry follow-up.

    Setting and participants: 5,350 randomly selected men from the general population aged 30, 40, 50, 60 or 70 years at baseline.

    Main Outcome measures: All-cause mortality, cardiovascular disease (CVD) mortality and cancer mortality.

    Results: 1,533 men died during the follow-up period; 428 from CVD and 480 from cancer.

    Cox proportional hazard models revealed that men in highest LH quartile had an increased all-cause mortality compared to lowest quartile (HR=1.32, 95%CI: 1.14 to 1.53). Likewise, increased quartiles of LH/T and estradiol increased the risk of all-cause mortality (HR=1.23, 95%CI: 1.06 to 1.43, HR=1.23, 95%CI: 1.06 to 1.43). No association to testosterone levels was found.

    Higher LH levels were associated with increased cancer mortality (HR=1.42, 95%CI: 1.10 to 1.84) independently of smoking status.

    Lower CVD mortality was seen for men with testosterone in the highest quartile compared to lowest (HR=0.72, 95%CI: 0.53 to 0.98). Furthermore, negative trends were seen for SHBG and free testosterone in relation to CVD mortality, however insignificant.

    Conclusion: The observed positive association of LH and LH/T, but not testosterone, with all-cause mortality suggests that a compensated impaired Leydig cell function may be a risk factor for death by all causes in men. Our findings underpin the clinical importance of including LH measurement in the diagnostic work-up of male patients seeking help for possible androgen insufficiency.
  13. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Hackett GI. testosterone Replacement Therapy and Mortality in Older Men. Drug Saf.

    While US testosterone prescriptions have tripled in the last decade with lower trends in Europe, debate continues over the risks, benefits and appropriate use of testosterone replacement therapy (TRT).

    Several authors blame advertising and the availability of more convenient formulations, whilst others have pointed out that the routine testing of men with erectile dysfunction (ED) (a significant marker of cardiovascular risk) and those with diabetes would inevitably increase the diagnosis of hypogonadism and lead to an increase in totally appropriate prescribing.

    They commented that this was merely an appropriate correction of previous under-diagnosis and under-treatment in line with evidence based guidelines.

    It is unlikely that persuasive advertising or convenient formulations could grow a market over such a sustained period if the treatment was not effective.

    Urologists and primary care physicians are the most frequent initiators of TRT usually for ED.

    Benefits are clearly established for sexual function, increase in lean muscle mass and strength, mood and cognitive function, with a possible reduction in frailty and osteoporosis.

    There remains no evidence that TRT is associated with increased risk of prostate cancer or symptomatic benign prostatic hyperplasia, yet the decision to initiate and continue therapy is often decided by urologists.

    The cardiovascular issues associated with TRT have been clarified by recent studies showing that therapy associated with clear increases in serum testosterone levels to the normal range is associated with reduced all-cause mortality.

    Studies reporting to show increased risk have been subject to flawed designs with inadequate baseline diagnosis and follow-up testing.

    Effectively, they have compared non-treated patients with under-treated or non-compliant subjects involving a range of different therapy regimes.

    Recent evidence suggests long-acting injections may be associated with decreased cardiovascular risk, but the transdermal route may be associated with potentially relatively greater risk because of conversion to dihydrotestosterone by the effect of 5-alpha reductase in skin.

    The multiple effects of TRT may add up to a considerable benefit to the patient that might be underestimated by the physician primarily concerned with his own specialty.

    In a response to concerns about the possible risks associated with inappropriate prescribing expressed by Public Citizen, the Food and Drug Administration (FDA) published a complete refutation of all the concerns, only to issue a subsequent bulletin of concern over inappropriate use, whilst confirming the benefits in treating men with established testosterone deficiency.

    No additional evidence was provided for this apparent change of opinion, but longer term safety data on testosterone products were strongly suggested. In contrast, the European Medicines Agency (EMA), in November 2014, concluded that "there is no consistent evidence of increased cardiovascular risk with testosterone products".

    This paper explores the most recent evidence surrounding the benefits and risks associated with TRT.
  14. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    · Despite the large volume of research on testosterone deficiency syndrome, there are still many unanswered questions.
    · The diagnosis of testosterone deficiency syndrome requires a combination of factors, including history, examination, biochemical testing and response to therapy.
    · Erectile dysfunction is one of the most common symptoms associated with testosterone deficiency and a justification for testosterone therapy, even in patients with comorbidities.
    · Discussion about goals of therapy is essential in making treatment decisions, particularly around fertility and symptom control in younger men.

    Hackett GI. Controversies in the diagnosis and management of testosterone deficiency syndrome. CMAJ.
  15. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Gooren L. Diagnosing hypogonadism and treating decisions in different parts of the world: shifts in patterns between 2006 and 2015. Aging Male.

    AIM: Variations in diagnosing and treating testosterone (T) deficiency between different regions of the world were analyzed in 2006, and repeated in 2010. At present, the changes since 2006 were analyzed.

    METHODS: About 731 physicians were interviewed in Europe, South Africa, Central and South America regarding factors determining:
    (1) prescription of T or withholding T,
    (2) factors in the long-term use of T and the role of T formulations therein,
    (3) awareness of the wider spectrum of action of T (cardiometabolic disease),
    (4) reimbursement of T and its impact on (continued) use and
    (5) best strategies for information on T for physicians.

    RESULTS: Total T was a key factor in identifying hypogonadism, but for >80% of physicians, clinical symptoms were weighed during diagnosis.



    CONCLUSION: More hypogonadal men are treated than before, but approximately 20% goes unidentified. Physicians have a greater awareness that T deficiency can be an element in cardiovascular and metabolic disease, but more education of physicians on diagnosis and treatment of hypogonadism are needed. Problems with reimbursement of T are barriers in the prescription of T and its use by patients.
  16. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Abd Alamir M, Ellenberg SS, Swerdloff RS, et al. The Cardiovascular Trial of the testosterone Trials: rationale, design, and baseline data of a clinical trial using computed tomographic imaging to assess the progression of coronary atherosclerosis. Coron Artery Dis.

    BACKGROUND: Data from prior studies have yielded inconsistent results on the association of serum testosterone levels with the risk for cardiovascular disease. There are no clinical trial data on the effects of testosterone replacement therapy on plaque progression.

    OBJECTIVE: We designed a study to investigate the effect of testosterone therapy on coronary artery plaque progression using serial coronary computed tomographic angiography (CCTA). In this paper, we describe the study design, methods, and characteristics of the study population.

    METHODS: The Cardiovascular Trial of the Testosterone Trials (TTrials; NCT00799617) is a double-blind, placebo-controlled trial of 1 year of testosterone therapy in men 65 years or older with clinical manifestations of androgen deficiency and unequivocally low serum testosterone concentrations (<275 ng/dl). CCTA performed at baseline and after 12 months of therapy will determine the effects of testosterone on the progression of the total volume of noncalcified plaques. All scans are evaluated at a central reading center by an investigator blinded to treatment assignment.

    RESULTS: A total of 165 men were enrolled. The average age is 71.1 years, and the average BMI is 30.7. About 9% of men had a history of myocardial infarction, 6% angina, and 10% coronary artery revascularization. A majority reported hypertension and/or high cholesterol; 31.8% reported diabetes. Total noncalcified plaque at baseline showed a slight but nonsignificant trend toward lower plaque volume with higher serum testosterone concentrations (P=0.12).

    CONCLUSION: The Cardiovascular Trial will test the hypothesis that testosterone therapy inhibits coronary plaque progression, as assessed by serial CCTA.
  17. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Christe N, Meier CA. Hypotestosteronaemia in the aging male: should we treat it? Swiss Med Wkly 2015;145:w14216.

    The term male hypogonadism is defined as the failure to maintain physiological concentrations of testosterone, a physiological quantity of sperm or the combination of both.

    Aetiologically, androgen deficiency can originate from the testes (primary hypogonadism) or from the hypothalamic-pituitary regulation of the testicular function (secondary hypogonadism).

    The causes of hypogonadism are very diverse and may be genetically determined (e.g. Klinefelter's syndrome) or acquired (tumours, infections, haemochromatosis).

    Classical hypogonadism linked to an underlying disease, such as a pituitary tumour, is a distinct indication for androgen substitution. But how about the aging male?

    It is known that there is a highly variable age-related decline in testosterone levels; whether this represents a variation of normality or has a true disease value requiring therapy has been disputed over more than a decade.

    The key questions surrounding this debate concern not only the age-dependent threshold for serum testosterone but, more importantly, the risks and benefits of testosterone replacement therapy in the aging male.

    We searched the literature for randomised controlled trials of testosterone administration in aging males with a size of at least 100 patients and a follow-up of at least 6 months, and identified eight studies. These studies mostly tried to evaluate the effect of testosterone on bone density, muscle strength and body composition, rather than clinically meaningful endpoints.

    Moreover, these trials have provided evidence for relevant cardiovascular adverse events in elderly men. This supports the need for further studies to define the treatment threshold for testosterone levels in the aging male, as well as with regard to the long-term risks and relevant benefits of testosterone therapy in this population.

    Until we have more solid data in aging males, testing for testosterone deficiency and testosterone replacement should remain reserved for patients with predisposing conditions, symptoms and signs of bona fide hypogonadism.
  18. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Michaud JE, Billups KL, Partin AW. testosterone and prostate cancer: an evidence-based review of pathogenesis and oncologic risk. Ther Adv Urol 2015;7(6):378-87.

    Testosterone plays a central role in male development and health. Likewise, androgen deficiency, or hypogonadism, is associated with a variety of symptoms including decreased energy, diminished libido and erectile dysfunction, among others. Male androgen levels steadily decline with age, and, in a subset of symptomatic older men, can result in late-onset hypogonadism (LOH).

    Over the last decade, increased awareness of hypogonadism among patients and providers has led to a significant rise in the use of testosterone replacement therapy (TRT) for hypogonadism, and especially in LOH. Accompanying the rise in TRT are concerns of potential adverse effects, including cardiovascular risks and the promotion of prostate cancer.

    The 'androgen hypothesis' asserts that prostate cancer development and progression is driven by androgens, and thus TRT has the theoretical potential to drive prostate cancer development and progression.

    In this review, we examine existing data surrounding testosterone and prostate cancer. There is significant evidence that androgens promote prostate cancer in experimental systems. However, there is no clear evidence that elevations in endogenous testosterone levels promote the development of prostate cancer in humans.

    As a result of experimental and historical data on the progression of prostate cancer following TRT, there has been widespread belief that TRT will promote disease progression in prostate cancer patients.

    Despite these fears, there are a growing number of studies demonstrating no increase in prostate cancer incidence among men on TRT. Furthermore, in studies involving a small number of patients, there has been no discernable increase in disease progression in prostate cancer patients on TRT.

    While data from large, prospective, randomized, controlled trials are absent, TRT in select prostate cancer patients is likely safe. In the end, the use of TRT in prostate cancer patients is still considered experimental and should only be offered after well-informed shared decision making and with close monitoring.
  19. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Gencer B, Mach F. testosterone: a hormone preventing cardiovascular disease or a therapy increasing cardiovascular events? Eur Heart J.

    Decreasing testosterone levels with ageing is a well-known condition in older men named 'low T', 'manopause', or hypogonadism.

    Observational studies suggested an association between low endogenous testosterone levels and a high cardio-metabolic profile (increased blood pressure, dyslipidaemia, insulin resistance, atherosclerosis, thrombosis), as well as a modest increase in total and cardiovascular (CV) mortality.

    Controversies persist regarding the need for screening 'low T' in older men, as well as what precisely should be the indication(s) for testosterone replacement therapy.

    So far, no data have shown that normalization of testosterone levels reduce CV events.

    Although testosterone replacement therapy seems to have beneficial effects on male quality of life or physical condition, some data suggest serious adverse events, such as CV events.

    In addition, there is a lack of consensus on the threshold for treatment indication in men with non-specific symptoms or borderline levels of testosterone.

    Available data from clinical practice setting suggest an increase in testosterone prescription over time and possible overtreatment.

    In recent years, pharmaceutical companies have promoted 'low T' as a treatable disease, suggesting that testosterone replacement may help restore energy, positive mood and sexuality, and despite ageing.

    Currently, well-designed, adequately powered randomized controlled trials are needed to assess the impact of testosterone replacement therapy on CV clinically relevant CV outcomes within age-specific ranges to strengthen the evidence for clinical practice guidelines.
  20. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Glueck C, Riaz R, Prince M, Freiberg R, Wang P. testosterone Therapy Can Interact With Thrombophilia, Leading to Osteonecrosis. ORTHOPEDICS. 2015; 38: e1073-e1078. Testosterone Therapy Can Interact With Thrombophilia, Leading to Osteonecrosis | Orthopedics

    Although this effect is not widely recognized, testosterone therapy can interact with thrombophilia, causing osteonecrosis. In 12 men and 4 women who had idiopathic osteonecrosis a median of 6 months after the onset of testosterone therapy, the authors examined the interaction between testosterone therapy and previously undiagnosed thrombophilia. The authors hypothesized that patients who had osteonecrosis after starting testosterone therapy were more likely than 110 normal control subjects or 48 patients who had osteonecrosis and were not receiving testosterone therapy to have thrombophilia. Measures of thrombophilia included Factor V Leiden, prothrombin, PAI-1 gene mutations, Factor VIII, Factor XI, anticardiolipin antibody immunoglobulin G or immunoglobulin M, and homocysteine values. In 10 cases, osteonecrosis occurred 6 months or less after the onset of testosterone therapy, and in all 16 cases, it occurred after a median of 6 months of testosterone therapy. Of the 16 cases, 5 (31%) were Factor V Leiden heterozygotes vs 2 of 109 (2%) healthy control subjects (P=.0003) and 4 of 48 patients who had osteonecrosis and were not receiving testosterone therapy (P=.04). Of the 16 cases, 4 (25%) had high (>150%) Factor VIII levels vs 7 of 103 (7%) healthy control subjects (P=.04), and 3 (19%) had high (>150%) Factor XI levels vs 3 of 101 (3%) healthy control subjects (P=.03). Of the 16 patients with osteonecrosis, 14 (88%) had at least 1 abnormal procoagulant value (of the 8 measured) vs 47 of 110 (43%) healthy control subjects (P=.0009). Of the 5 men whose serum estradiol level was measured while they were receiving testosterone therapy, this level was high (≥42.6 pg/mL) in 4. When testosterone therapy is given to patients with thrombophilia, they are at increased risk for osteonecrosis.