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6/10/2016
1
Low Testosterone:
When to Test and When to Treat?
Megan Curtis, MD
Swedish First Hill Family Medicine
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Objectives
• Review media and marketing portrayal of “low T” and
testosterone therapy
• Recognize clinical indications to test for low testosterone
• Review the evidence for benefits and risks of testosterone
therapy
Scope: natal males with a history of normal puberty
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Two Case Scenarios
1. Elmer: 75 yo male c/o fatigue, poor libido, and “losing
muscle”.
1. Chester: 50 yo male c/o loss of body hair, decreased
testicular size, and fatigue.
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“It’s not you... It could be Low T.”
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Prescribing Practices: FDA
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Prescriptions in Men > 40 yo
0.8% (2001) 3% (2011)
55,000 rx/mo (2000) 550,000 (2014)
25-70% of patients have no baseline testosterone level
FDA Advisory Committee Meeting on Testosterone Replacement Therapy, 2014
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Annual Testosterone
Drug Revenue in the U.S.
2002: $324 million
2013: $2.4 billion
FDA Advisory Committee Meeting on Testosterone Replacement Therapy, 2014
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FDA Advisory Committee Meeting on Testosterone
Replacement Therapy, September 17, 2014
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Baltimore Longitudinal
Study of Aging
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Baltimore Longitudinal Study of Aging
Figure 1: Effects of age and date on
serum testosterone
Figure 3: Hypogonadism in
aging men
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The European Male Aging Study
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The European Male Aging Study
3500 men, 8 centers
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The European Male Aging Study
3500 men, 8 centers
Hypogonadism: 3-5%
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Male Aging ≠ hypogonadism
….so what does define hypogonadism?
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Hypogonadism – Endocrine Society Definition:
“We recommend making a diagnosis of androgen deficiency
only in men with consistent symptoms and signs and
unequivocally low serum testosterone levels.”
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Non-specific signs/symptoms
• Low Energy
• Mood changes
• Concentration/memory
• Sleep disturbance
• Mild anemia
• Decreased muscle Mass
• Increased body fat, BMI
• Declining physical/work performance
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Sexual
development
Libido
Gynecomastia
Loss of body hair
Decreased
testicular size
Fertiity
Vasomotor
Bone density
Hypogonadism:
Specific signs and symptoms
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When to measure serum
total testosterone:
EARLY MORNING…
Snyder, PJ. Clinical Features and Diagnosis of Male Hypogonadism. UpToDate
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When to measure serum
total testosterone:
EARLY MORNING… x2!
Snyder, PJ. Clinical Features and Diagnosis of Male Hypogonadism. UpToDate
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FDA Advisory Committee Meeting on Testosterone Replacement Therapy, 2014
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Treating symptoms in the absence of
hypogonadism…
… is using testosterone as an anabolic steroid.
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Endocrine Society
“Testosterone treatment is not approved by the Food
and Drug Administration to improve strength,
athletic performance, appearance or normal
problems associated with aging.”
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Snyder, PJ. Clinical Features and Diagnosis of Male Hypogonadism. UpToDate
Primary vs. Secondary Hypogonadism
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Snyder, PJ. Clinical Features and Diagnosis of Male Hypogonadism. UpToDate
Additional workup: • LH
• FSH
• Prolactin
• TSH
Consider MRI
Primary vs. Secondary Hypogonadism
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*Modifiable
Primary =
Testicular
[High FSH and
LH]
Secondary =
hypothalamic/pituitar
y
[Low/normal FSH
and LH]
Congenital • Kleinfelter
• Undescended
testes*
• Idiopathic
hypogonadotropic
hypogonadism
• Kallman syndrome
Acquired • Opiates*
• Marijuana*
• Testicular trauma
• Mumps orchitis
• Radiation therapy
• Intracranial tumors
• Radiation/surgery to
sellar region
• Infiltrative/systemic
illnesses
• Critical illness
• Glucocorticoid therapy
• Obesity*
• Insulin resistance*
• Androgen supplements*
• Obstructive sleep apnea*
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Address Modifiable Causes First
• Obesity, insulin resistance
• Cortisol/steroids
• Obstructive sleep apnea
• Opiates
• Marijuana
• Supplements/DHEA
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Obesity and Sleep Apnea:
More questions than answers
Obesity
Obstructive
Sleep Apnea
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Obesity and Sleep Apnea:
More questions than answers
Obesity
Obstructive
Sleep Apnea
Hypogonadism
Insulin
resistance
Metabolic
Syndrome
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Obesity and Sleep Apnea:
More questions than answers
Obesity
Obstructive
Sleep Apnea
Hypogonadism
Insulin
resistance
Metabolic
Syndrome
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Obesity and Sleep Apnea:
More questions than answers
Obesity
Obstructive
Sleep Apnea
Hypogonadism
Insulin
resistance
Metabolic
Syndrome
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WARNING –
Underlying Illnesses
Ahead
– Insulin resistance
– OSA
– Depression
– Hypothyroidism
– Substance abuse
– Erectile dysfunction
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Weighing the Benefits and Risks
with your Patients
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Benefits* Libido
Erectile function
Hair growth
Muscle vs fat mass
Falls/physical functioning
Mood
Bone mineral density
Fragility fractures
Metabolic syndrome
Cognition
Insulin sensitivity
Cardiovascular risk
*Most elicited through treatment of young, hypogonadal men (e.g. s/p orchiectomy)
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Contraindications
• Breast or prostate cancer
• PSA > 4.0
• High risk for prostate cancer*
• Poorly controlled CHF
• Hct > 50
• Severe untreated OSA
• Desire for fertility
• Severe LUT symptoms
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Adverse events, risks • Erythrocytosis
• Acne, oily skin
• Overdiagnosis of subclinical prostate cancer
• Growth of metastatic prostate cancer
• Infertility, decreased sperm count
• Specific formulation concerns
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Adverse events, risks • Erythrocytosis
• Acne, oily skin
• Overdiagnosis of subclinical prostate cancer
• Growth of metastatic prostate cancer
• Infertility, decreased sperm count
• Specific formulation concerns
*Cardiovascular risk and death*
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March 2013
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Reviewing Evidence for Risk
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Basaria et al.
• 200 community dwelling men ≥ 65 with mobility limitations
randomized to testosterone gel or placebo gel for 6 months
• Trial stopped early due to increased CV risk in the treatment
group
• CV risk was higher with polycythemia as well as higher
testosterone levels
• Multiple limitations…
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Basaria et al. Adverse events associated with testosterone administration. N Engl J Med. 2010
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Basaria et al. Adverse events associated with testosterone administration. N Engl J Med. 2010
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Xu et al. BMC Med. 2013
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What about screening?
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So is there a role for screening?
Universally: NO
• There are few special populations to consider screening
with history
• Asymptomatic not hypogonadism
• Risk vs. benefit still unclear
• No trials show screening affects patient-oriented outcomes
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Endocrine Society, 2010
“We recommend against screening for androgen deficiency in
the general population.”
“We suggest that clinicians not use the available case-finding
instruments for detection of androgen deficiency in men
receiving health care for unrelated reasons.”
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Special Populations
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AUA Position Statement on
Testosterone Therapy
“Testosterone therapy is appropriate treatment for patients
with clinically significant hypogonadism, including those with idiopathic
clinical hypogonadism that may or may not be age-related, after full discussion of
potential adverse effects. Patients should understand that treatment requires follow-up
and medical monitoring. Testosterone therapy in the absence of
hypogonadism is inappropriate.”
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The Bottom Line
“Low T” is a marketing ploy.
Low testosterone is a lab value.
Hypogonadism is a clinical diagnosis.
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Take Home Points
• “Low T” ≠ hypogonadism
• Universal screening is not appropriate
• Evaluate for acquired/secondary causes
• Discuss benefits and risks of testosterone treatment with
your patients
• Use a clinical guide for treatment
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References
• Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, Zhang A, Choong K,
Lakshman KM, Mazer NA, Miciek R, Krasnoff J, Elmi A, Knapp PE, Brooks B, Appleman E, Aggarwal S, Bhasin G, Hede-
Brierley L, Bhatia A, Collins L, LeBrasseur N, Fiore LD, Bhasin S. Adverse events associated with testosterone administration. N
Engl J Med. 2010 Jul 8;363(2):109-22. doi: 10.1056/NEJMoa1000485. Epub 2010 Jun 30. PubMed PMID: 20592293; PubMed
Central PMCID: PMC3440621.
• Choosing Wisely, An Initiative of the ABIM foundation. http://www.choosingwisely.org/clinician-lists/#keyword=testosterone.
• Finkle WD, Greenland S, Ridgeway GK, et al. Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone
Therapy Prescription in Men. Gong Y, ed. PLoS ONE. 2014;9(1):e85805. doi:10.1371/journal.pone.0085805.
• Fugh-Berman A. Should family physicians screen for testosterone deficiency in men? No: screening may be harmful, and benefits
are unproven. Am Fam Physician. 2015 Feb 15;91(4):226-8. PubMed PMID: 25955622.
• Giagulli VA, Kaufman JM, Vermeulen A. Pathogenesis of the decreased androgen levels in obese men. J Clin Endocrinol Metab.
1994 Oct;79(4):997-1000. PubMed PMID: 7962311.
• Hammond GL. Diverse roles for sex hormone-binding globulin in reproduction. Biol Reprod. 2011 Sep;85(3):431-41. doi:
10.1095/biolreprod.111.092593. Epub 2011 May 25. Review. PubMed PMID: 21613632; PubMed Central PMCID:
PMC4480437.
• Handelsman DJ. Global trends in testosterone prescribing, 2000-2011: expanding the spectrum of prescription drug misuse. Med
J Aust. 2013 Oct 21;199(8):548-51. PubMed PMID: 24138381.
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References
• Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR; Baltimore Longitudinal Study of Aging. Longitudinal effects of
aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol
Metab. 2001 Feb;86(2):724-31. PubMed PMID: 11158037.
• Heidelbaugh JJ. Should family physicians screen for testosterone deficiency in men? Yes: screening for testosterone deficiency
is worthwhile for most older men. Am Fam Physician. 2015 Feb 15;91(4):220-1. PubMed PMID: 25955621.
• Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH. Testosterone deficiency is associated with increased risk of
mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol. 2013 Oct
21;169(6):725-33. doi: 10.1530/EJE-13-0321. Print 2013 Dec. PubMed PMID: 23999642.
• Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low
testosterone levels. J Clin Endocrinol Metab. 2012 Jun;97(6):2050-8. doi: 10.1210/jc.2011-2591. Epub 2012 Apr 11. PubMed
PMID: 22496507.
• Petteloud, N, Crowley, WF. Congenital Gonadotropin-releasing Hormone Deficiency (idiopathic hypogonadotropic
hypogonadism). In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on June 2, 2016).
• Raynor MC, Carson CC, Pearson MD, Nix JW. Androgen deficiency in the aging male: a guide to diagnosis and testosterone
replacement therapy. Can J Urol. 2007;14 Suppl 1:63-8.
• Shalender Bhasin, Glenn R. Cunningham, Frances J. Hayes, Alvin M. Matsumoto, Peter J. Snyder, Ronald S. Swerdloff, and
Victor M. Montori. Testosterone Therapy in Men with Androgen Deficiency Syndromes: An Endocrine Society Clinical
Practice Guideline. The Journal of Clinical Endocrinology & Metabolism 2010 95:6.
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References
• Snyder, PJ. Causes of Primary Hypogonadism in Males. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on
June 2, 2016).
• Snyder, PJ. Causes of Secondary Hypogonadism in Males. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed
on June 2, 2016).
• Snyder, PJ. Clinical Features and Diagnosis of Male Hypogonadism. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA.
(Accessed on June 2, 2016).
• Snyder, PJ. Testosterone Treatment of Male Hypogonadism. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed
on June 2, 2016).
• Trumble BC, Cummings DK, O'Connor KA, Holman DJ, Smith EA, Kaplan HS, Gurven MD. Age-independent increases in
male salivary testosterone during horticultural activity among Tsimane forager-farmers. Evol Hum Behav. 2013 Sep 1;34(5). doi:
10.1016/j.evolhumbehav.2013.06.002. PubMed PMID: 24187482; PubMed Central PMCID: PMC3810999.
• US. Food and Drug Administration: Bone, Reproductive and Urologic Drugs Advisory Committee (formerly Reproductive
Health Drugs Advisory Committee). Advisory Committee Industry Briefing Document Testosterone Replacement Therapy.
Meeting September 17, 2014. Accessed June 2, 2016 at
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/reproductivehealthdrugsadvisorycom
mittee/ucm412537.pdf.
• Vigen R, O'Donnell CI, Barón AE, Grunwald GK, Maddox TM, Bradley SM, Barqawi A, Woning G, Wierman ME,
Plomondon ME, Rumsfeld JS, Ho PM. Association of testosterone therapy with mortality, myocardial infarction, and stroke in
men with low testosterone levels. JAMA. 2013 Nov 6;310(17):1829-36. doi: 10.1001/jama.2013.280386. Erratum in: JAMA.
2014 Mar 5;311(9):967. PubMed PMID: 24193080.
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References
• Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, O'Neill TW, Bartfai G, Casanueva FF, Forti G, Giwercman A, Han
TS, Kula K, Lean ME, Pendleton N, Punab M, Boonen S, Vanderschueren D, Labrie F, Huhtaniemi IT; EMAS Group.
Identification of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. 2010 Jul 8;363(2):123-35. doi:
10.1056/NEJMoa0911101. Epub 2010 Jun 16. PubMed PMID: 20554979.
• Wu FC, Tajar A, Pye SR, Silman AJ, Finn JD, O'Neill TW, Bartfai G, Casanueva F, Forti G, Giwercman A, Huhtaniemi IT, Kula
K, Punab M, Boonen S, Vanderschueren D; European Male Aging Study Group. Hypothalamic-pituitary-testicular axis
disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin
Endocrinol Metab. 2008 Jul;93(7):2737-45. doi: 10.1210/jc.2007-1972. Epub 2008 Feb 12. PubMed PMID: 18270261.
• Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review
and meta-analysis of placebo-controlled randomized trials. BMC Med. 2013 Apr 18;11:108. doi: 10.1186/1741-7015-11-108.
PubMed PMID: 23597181; PubMed Central PMCID: PMC3648456.
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Questions?
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Colbert Report Video Clip
• http://www.cc.com/video-clips/q3aiti/the-
colbert-report-low-t---low-o