Testosterone Deficiency
TESTOSTERONE
AUA GUIDELINE KEY POINTS:
AUA 2018 guideline has a cutoff of 300ng/dl for total testosterone.
Patients should be informed that testosterone therapy may result in improvements in erectile function, low sex drive, anemia, bone mineral density, lean body mass, and/or depressive symptoms. Patients should be informed that the evidence is inconclusive whether testosterone therapy improves cognitive function, measures of diabetes, energy, fatigue, lipid profiles, and quality of life measures. Prior to initiating treatment, clinicians should counsel patients that, at this time, there is no definitive link to increased risk of VTE and it cannot be stated definitively whether testosterone therapy increases or decreases the risk of cardiovascular events (e.g., myocardial infarction, stroke, cardiovascular-related death, all-cause mortality). Low testosterone is associated with increased risk of MI, CVA, HTN, HLD and obesity. Testosterone therapy should not be commenced for a period of three to six months in patients with a history of a cardiovascular events. Clinicians may use aromatase inhibitors, human chorionic gonadotropin, selective estrogen receptor modulators, or a combination thereof in men with testosterone deficiency desiring to maintain fertility. Long-acting IM testosterone resulted in a mean increase in Hb levels of 1.4 mg/dL compared to 1.6 mg/dL with short-acting IM testosterone, 0.9 mg/dL with transdermal preparations, and 0.7 mg/dL with topical patches. (2)
ISSM states diagnosis and therapeutic benefit are more likely at levels lower testosterone than 231ng/dl and men with 346ng/dl or higher are unlikely to have testosterone deficiency and benefit from treatment.
Endocrine Society states (1):
DIAGNOSIS
AUA 2018 guideline has a cutoff of 300ng/dl for total testosterone.
- Need 2 morning results from the same laboratory (Repeat measures can fluctuate 65-153%) (5)
- Consider measuring total testosterone in patients with a history of unexplained anemia, bone density loss, diabetes, exposure to chemotherapy, exposure to testicular radiation, HIV/AIDS, chronic narcotic use, male infertility, pituitary dysfunction, and chronic corticosteroid use even in the absence of symptoms or signs associated with testosterone deficiency.
- Serum prolactin levels should be measured in patients with low testosterone levels combined with low or low/normal luteinizing hormone levels.
- Serum estradiol should be measured in testosterone deficient patients who present with breast symptoms or gynecomastia prior to the commencement of testosterone therapy.
- PSA should be measured in men over 40 years of age prior to commencement of testosterone therapy to exclude a prostate cancer diagnosis.
- Defines success as achievement of therapeutic testosterone levels to the normal physiologic range of 450 -600 ng/dL (middle tertile of the reference range for most labs) accompanied by symptom/sign improvement/resolution.
Patients should be informed that testosterone therapy may result in improvements in erectile function, low sex drive, anemia, bone mineral density, lean body mass, and/or depressive symptoms. Patients should be informed that the evidence is inconclusive whether testosterone therapy improves cognitive function, measures of diabetes, energy, fatigue, lipid profiles, and quality of life measures. Prior to initiating treatment, clinicians should counsel patients that, at this time, there is no definitive link to increased risk of VTE and it cannot be stated definitively whether testosterone therapy increases or decreases the risk of cardiovascular events (e.g., myocardial infarction, stroke, cardiovascular-related death, all-cause mortality). Low testosterone is associated with increased risk of MI, CVA, HTN, HLD and obesity. Testosterone therapy should not be commenced for a period of three to six months in patients with a history of a cardiovascular events. Clinicians may use aromatase inhibitors, human chorionic gonadotropin, selective estrogen receptor modulators, or a combination thereof in men with testosterone deficiency desiring to maintain fertility. Long-acting IM testosterone resulted in a mean increase in Hb levels of 1.4 mg/dL compared to 1.6 mg/dL with short-acting IM testosterone, 0.9 mg/dL with transdermal preparations, and 0.7 mg/dL with topical patches. (2)
ISSM states diagnosis and therapeutic benefit are more likely at levels lower testosterone than 231ng/dl and men with 346ng/dl or higher are unlikely to have testosterone deficiency and benefit from treatment.
Endocrine Society states (1):
DIAGNOSIS
- Diagnosis with 2 or more morning total testosterone
- Free testosterone should be measured when SHBG may be altered (obesity, DM, nephrotic syndrome, hypothyroidism, hyperthyroidism, acromegaly, older age, HIV, cirrhosis, hepatitis, if taking certain convusants and in patients taking steroids, estrogens or progestins
- If low T, measure FSH/LH
- Not recommended for men planning on fertility in the near term, with breast or prostate cancer, a palpable nodule or induration on DRE, PSA >4.0 (or PSA >3.0 w/ high risk for prostate cancer), hematocrit >48% (>50% if at high altitude), untreated OSA, severe LUTS, uncontrolled CHF, MI or CVA w/in last 6 mo, thrombophilia
- Monitor CBC, T levels, PSA levels several times a year 1st year, then annually
PHYSIOLOGY
Bound to albumin (50%, loosely-bound), sex hormone-binding globulin ([SHBG], 44%, tightly-bound), corticotropin-binding globulin (4%, loosely-bound), and approximately 2% circulates as free testosterone. (3) Among men with traditional (10p.m. to 6a.m.) sleep patterns, peak testosterone values occur around 3-8a.m., with 32-39% of the diurnal total decline occurring within the first 30 minutes of waking. (2) Total testosterone values obtained at 4p.m. in men aged 30-40 years were 20-25% lower than measurements takes at 8a.m., while men aged 70 years experienced only a 10% decline between the two time points. (4) In a small study of young men with acute respiratory infections, mean total testosterone levels declined by 10%, with some cohorts experiencing reductions of up to 30%. (6)
LOW ENERGY AND FATIGUE
While research doesn't show significant improvement in energy levels or fatigue, it is possible testosterone therapy (TT) improves these symptoms (2)
ERECTILE FUNCTION
Testosterone shows statistically significant improvements in the erectile function in hypogonadal men. (12) As of 2018, there is no good data on what % of men respond to testosterone therapy. (2)
DEVELOPMENT OF NEW PROSTATE CANCER
A meta-analysis of 7 RCTs showed that there was no significant increase in the rate of a prostate cancer diagnosis in older, testosterone deficient men who were treated with testosterone compared to placebo. (2) Other meta-analysis support this finding, although there are no RCT to support this finding. (16,17)
HISTORY OF PROSTATE CANCER - POST PROSTATECTOMY
TT can be considered s/p radical prostatectomy with favorable pathology (e.g., negative margins, negative seminal vesicles, negative lymph nodes), and who have undetectable PSA postoperatively. (2) Current studies show no conclusive increase in risk in post prostatectomy with undetectable biochemical recurrence. (18,19,20)
HISTORY OF PROSTATE CANCER - POST RADIATION
Retrospective studies suggest TT is unlikely to cause progression of PC in most patients w/ h/o radiation. (2) However, there is data that suggests patients w/ high risk PC s/p radiation may be at increased risk for BCR w/ TT (21)
VENOUS THROMBOEMBOLISM (VTE)
There is no definitive evidence linking TT to a higher incidence of VTE. The 2014 FDA warning was based on anecdotal accounts and not peer reviewed evidence. Multiple retrospective studies shown no association between, (22,23,24,25) one suggests increased association during first 6 months. (26)
CARDIOVASCULAR RISK
Current evidence consistently demonstrates that low testosterone levels that are untreated have an association with increased risk of cardiovascular event (CVE). Whether or not TT increases risk of CVE has not been determined. Some RCT show an increased risk, some show no change in risk and some show a decreased risk. (2)
DEPRESSION
Older men w/ low testosterone are 3 times more likely to have increased risk of depression. (7) Studies suggest testosterone therapy may mildly decrease depression, make no change in anxiety and increase mood regardless of baseline. (2)
OBESITY
Men who are obese (BMI ≥30) or who have increased waist circumference (>40 inches) should have their testosterone levels checked according to endocrine societies. Obese men are almost five times more likely to have low testosterone than men who are not obese (OR=4.89; CI: 2.35, 10.17). (2)
DIABETES
The American Association of Clinical Endocrinologists (AACE) recommends that men with type 2 diabetes be evaluated for testosterone deficiency.(8) The prevalence of low testosterone levels (defined as total testosterone of <300 ng/dL) was 24.5% in diabetic men as compared to 12.6% in the rest of the sample (p<0.0001), a difference that remained significance after adjustment for age and BMI. (10) There is the possibility of improvement in glucose control, however most data suggest A1C does not improve with testosterone therapy.
ANEMIA
Patients w/ history of unexplained anemia should have their testosterone tested. Multiple RCT show a 1.2 g/dL increase in Hb.
BONE DENSITY
Men who present with low-trauma bone fractures (LTBF) should have their testosterone measured. Consider baseline bone densitometry (DEXA) scan. An analysis of 6 studies showed that BMD increased significantly (0.41 g/cm2; CI 0.11, 0.72) w/ testosterone therapy. (2) One RCT of patients with osteoporosis with history of fracture showed 3-4% increase in BMD in the lumbar spine and femoral neck with testosterone therapy at 24mo of therapy. (13) RCT show up to an estimated 5% per year increase in BMD in men on testosterone therapy. (14)
VARICOCELE
A systematic review found that varicocele ligation results in significant improvement in testosterone levels in some men, with a mean improvement of approximately 100 ng/dL. (9)
SEX DRIVE
Sex drive is complex and hard to quantify. Studies show a non-significant trend towards improvement of sex drive. (2)
WEIGHT/BMI/MUSCLE MASS
Meta-analyses has shown increases in lean muscle mass with testosterone therapy and inconsistent results on overall BMI. (2)
COGNITIVE FUNCTION
Testosterone therapy has indeterminate effect on cognitive function. The data shows there is the possibility of improvement; however, most RCT do not show a benefit. (2)
LIPID LEVELS
Meta-analysis of RCT shows no improvement overall with some possible improvement in triglycerides and cholesterol in patients with testosterone deficiency. (2)
SPERMATOGENESIS
A meta-analysis showed the probability of post-testosterone therapy recovery of sperm concentration to >20 million/mL was 67% within 6 months, 90% within 12 months, 96% within 16 months, and 100% within 24 months. (15)
ESRD/HD TREATMENT
Testosterone gel has been shown effective in the treatment of ED in hypogonadal hemodialysis patients has been showed in a cohort of 96 men with ESRD. (27)
OTHER
History of radiation to pelvis/testicles, chemotherapy, HIV, opiod use, infertility, prolactin derangement and chronic steroids are all associated with testosterone deficiency. Men with total testosterone levels of <150 ng/dL in combination with a low or low/normal LH should undergo a pituitary MRI regardless of prolactin levels, as non-secreting adenomas may be identified. (11)
MEN WITH SYMPTOMS BUT NORMAL RANGE TESTSOSTERONE
In clinical practice there are men who have total testosterone levels >300 ng/dL who are highly symptomatic and who have anecdotally experienced symptom/sign improvement with testosterone therapy. The Panel urges clinicians to use their clinical judgment in the management of such patients. One strategy is to further evaluate patients using adjunctive tests, which might strengthen an argument for a short-term trial of testosterone therapy. (2)
- Sargis, Robert M., and Andrew M. Davis. "Evaluation and Treatment of Male Hypogonadism." JAMA 319.13 (2018): 1375-1376.
- http://www.auanet.org/guidelines/evaluation-and-management-of-testosterone-deficiency?utm_medium=email&utm_campaign=MEM
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- hores MM, Moceri VM, Sloan KL et al: Low testosterone levels predict incident depressive illness in older men: effects of age and medical morbidity. J Clin Psychiatry 2005; 66: 7.
- Garvey WT, Mechanick JI, Brett EM et al: American Association of Clinical Endocrinologists and American College of Endocrinology comprehensive clinical practice guidelines for medical care of patients with obesity. Endocr Pract 2016; 22 Suppl 3: 1.
- Li F, Yue H, Yamaguchi K et al: Effect of surgical repair on testosterone production in infertile men with varicocele: a meta-analysis. Int J Urol 2012; 19: 149.
- Corona G, Mannucci E, Petrone L et al: Association of hypogonadism and type II diabetes in men attending an outpatient erectile dysfunction clinic. Int J Impot Res 2006; 18: 190.
- Citron JT, Ettinger B, Rubinoff H et al: Prevalence of hypothalamic-pituitary imaging abnormalities in impotent men with secondary hypogonadism. J Urol 1996; 155: 529.
- Corona G, Isidori AM, Buvat J et al: Testosterone supplementation and sexual function: a meta-analysis study. J Sex Med 2014; 11: 1577.
- Wang YJ, Zhan JK, Huang W et al: Effects of low-dose testosterone undecanoate treatment on bone mineral density and bone turnover markers in elderly male osteoporosis with low serum testosterone. Int J Endocrinol 2013; 2013: 570413.
- Aversa A, Bruzziches R, Francomano D et al: Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study. Aging Male 2012; 15: 96.
- The probability of recovery of sperm concentration to >20 million/mL was 67% within 6 months, 90% within 12 months, 96% within 16 months, and 100% within 24 months.
- Eisenberg, Michael Louis. "Testosterone replacement therapy and prostate cancer incidence." The world journal of men's health 33.3 (2015): 125-129.
- Cui, Y., et al. "The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta-analysis." Prostate cancer and prostatic diseases 17.2 (2014): 132.
- Kaufman JM and Graydon RJ: Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol 2004; 172: 920.
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- Pastuszak AW, Khanna A, Badhiwala N et al: Testosterone therapy after radiation therapy for low, intermediate and high risk prostate cancer. J Urol 2015; 194: 1271.
- Maggi M, Heiselman D, Knorr J et al: Impact of testosterone solution 2% on ejaculatory dysfunction in hypogonadal men. J Sex Med 2016; 13: 1220.
- Baillargeon J, Urban RJ, Morgentaler A et al: Risk of venous thromboembolism in men receiving testosterone therapy. Mayo Clin Proc 2015; 90: 1038.
- Sharma R, Oni OA, Chen G et al: Association between testosterone replacement therapy and the incidence of DVT and pulmonary embolism: a retrospective cohort study of the veterans administration database. Chest 2016; 150: 563.
- Li H, Benoit K, Wang W et al: Association between use of exogenous testosterone therapy and risk of venous thrombotic events among exogenous testosterone treated and untreated men with hypogonadism. J Urol 2016; 195: 1065.
- Martinez C, Suissa S, Rietbrock S et al: Testosterone treatment and risk of venous thromboembolism: population based case-control study. BMJ 2016; 355: i5968.
- 35. Cangüven O, Aykose G, Albayrak S et all: Efficacy of testosterone gel in the treatment of erectile dysfunction in hypogonadal hemodialysis patients: a pilot study. Int J Impot Res. 2010;22:140–145.