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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