Low Testosterone: To Treat or Not to Treat?

Educational Objectives

The goal of this program is to improve the management ofhypogonadism. After hearing and assimilating this program, the clinician will be better able to:

1. Work up a patient with suspected low testosterone.

2. Treat a patient diagnosed with primary or secondary hypogonadism.

Summary

Testosterone (T): male hypogonadism defined as either low T or decrease in production of sperm; T circulates mostly bound to sex hormone-binding globulin (SHBG) or albumin; only ≈2% free; bioavailable T refers to free T plus amount of T bound to albumin

Measurement of total T: methods include liquid chromatography-tandem mass spectrometry (LC-MS/MS) and radioimmunoassay; lower limit of normal ≈300 ng/dL for most assays; usually accurate reflection of T status (exception for those with binding protein abnormality); factors that can lead to inaccurate or unreliable results when measuring total T include radioimmunoassay itself (in general, LC-MS/MS recommended as most accurate), age, concomitant illness, day-to-day variations, time of day (in young healthy men, T levels peak in morning and decline in afternoon and evening hours), and SHBG levels; total T in older men 50% to 66% of that in younger men

Conditions associated with altered SHBG: decreased SHBG — seen predominantly with obesity; also associated with nephrotic syndrome, hypothyroidism, and use of glucocorticoids, progestins, and anabolic steroids; increased SHBG — seen predominantly with aging; also associated with cirrhosis, use of estrogens, HIV, hyperthyroidism, and anticonvulsants; if SHBG abnormality suspected, check SHBG levels and consider calculation of free or bioavailable T (both can be measured directly or calculated from total T, SHBG, and albumin measurements)

Measurement of free or bioavailable T: most laboratories not able to perform direct measurement; therefore, calculator for free and bioavailable T recommended (available at www.issam.ch/freetesto.htm); calculated bioavailable T <70 ng/dL strongly suggests hypogonadism, and >100 ng/dL strongly suggests lack of disease; 70 to 100 ng/dL unclear

Diagnostic values: androgen deficiency — morning total T <200 ng/dL on ≥2 occasions with normal SHBG levels or bioavailable T <70 ng/dL; low T — morning total T 200 to 300 ng/dL or calculated bioavailable T 70 to 100 ng/dL

Primary vs secondary hypogonadism: primary hypogonadism — low T and elevated gonadotropins (follicle-stimulating hormone and luteinizing hormone); secondary hypogonadism — low T and low or inappropriately normal gonadotropins

Causes of primary hypogonadism: Klinefelter syndrome most common; vanishing testes or testicular torsion; secondary cause of testicular failure (eg, obesity, history of chemotherapy, orchitis, malnutrition or neurodegenerative illness, trauma)

Causes of secondary hypogonadism: Kallmann syndrome (usually associated with anosmia); Prader-Willi syndrome; pituitary tumors and disease; infiltrative diseases (eg, hemochromatosis); inflammatory diseases; other endocrine disorders (eg, hyperprolactinemia); anabolic steroid use; medications (eg, glucocorticoids, opioids)

Signs and symptoms of hypogonadism: less specific — lack of energy and motivation; depression; poor concentration and memory; sleep disturbances; mild anemia; increased body fat; decreased lean body mass; diminished physical or work performance; more specific — low libido; sexual dysfunction; breast discomfort; gynecomastia; eunuchoid body habitus; loss of body hair; small or shrinking testes; history of infertility; height loss or low-trauma fracture; hot flashes or sweating

Conditions associated with high prevalence of hypogonadism: pituitary tumor or sellar mass, or history of pituitary irradiation; long-term use of glucocorticoid or opioid; HIV; end-stage renal disease; moderate-to-severe chronic obstructive pulmonary disease; infertility; diabetes mellitus; OP

Screening for hypogonadism: not recommended for general population but may be considered in persons at high risk

Hypogonadism in older men: diagnosis and treatment highly controversial in men age ≥65 yr; T levels decline with normal aging, and no consensus on what constitute normal values; T therapy potentially benefits libido, erectile function, body composition, muscle strength, and BMD, but concerns about adverse events; little consensus on whether to treat older patients (measure SHBG levels and assess bioavailable T to help guide management)

Work-up for suspected low T: obtain patient history and perform physical examination; look for signs and symptoms; check morning total T; if normal, can assume patient does not have hypogonadism (unless low SHBG levels suspected); if low, exclude reversible causes and repeat test; do semen analysis if patient relatively young, unsure about diagnosis, or concerned about fertility; once low T confirmed, determine whether hypogonadism primary or secondary; karyotype analysis recommended if clinically relevant; in patient with secondary hypogonadism, screen for other pituitary hormone deficiencies, check iron indices to look for hemochromatosis, and perform pituitary magnetic resonance imaging if total T <150 ng/dL (speaker uses threshold of <200 ng/dL) or patient has panhypopituitarism, elevated prolactin, or signs and symptoms of other pituitary hormone deficiency

Therapy: goal to achieve total T level in midnormal range (500-600 ng/dL for young men and 400-500 ng/dL for older men; depending on age and comorbidities, speaker might aim for 300-400 ng/dL)

Preparations: injectable T — administered weekly or biweekly; need to check T levels midway between injections; transdermal patch (Androderm) — typically applied at night over skin of back, thigh, or upper arm; recommended to check T morning level 3 to 12 hr after application; gels — Androgel and Testim come in 2 formulations (1% and 1.62%) and available in pump and packets; 1% formulation can be applied to shoulders or abdomen, but 1.62% should only be applied to shoulders; T levels checked in morning just before application; Fortesta applied to medial thigh, and T levels checked 2 hr after application; topical solution (Axiron) — applied under arm; buccal tablets (Striant) — option for patients who cannot tolerate other formulations

Factors in choosing preparation: cost; insurance coverage; compliance; if adverse reaction to patch, can switch to gel; injectable T can sometimes cause mood changes and pain at injection site; transference concerns (gel); concerns about abuse (contraindication to injectable preparation)

Potential adverse effects: more common — erythrocytosis; increase in hematocrit; acne and oily skin; detection of subclinical or growth of metastatic prostate cancer; reduction in sperm count; less common — development or worsening of gynecomastia; worsening of male pattern balding and benign prostatic hyperplasia (BPH); development of breast cancer; induction or worsening of obstructive sleep apnea (OSA; common cause of secondary hypogonadism)

Contraindications: prostate cancer or nodule; breast cancer; unexplained rise in prostate-specific antigen (PSA); elevated hematocrit; hyperviscosity; untreated OSA; severe symptoms of BPH; congestive heart failure

Precautions: monitor T levels (evaluate 2-3 mo after initiation of therapy and then at least annually); check hematocrit at baseline, 3 mo, and then annually; monitoring of BMD recommended in patient with truly low levels of T (screening measurement at baseline and evaluation every 1-2 yr); digital rectal examination and PSA test before initiation of therapy, at 3 mo, and in accordance with prostate cancer guidelines (typically every 12 mo); refer patient on therapy to urology if he has abnormal urologic examination, develops severe symptoms of BPH, or significant rise in PSA

 

Readings

Basaria S: Male hypogonadism. Lancet 2013 Oct 9. pii: S0140-6736(13)61126-5; Biundo B: Treatment options for male hypogonadism. Int J Pharm Compd 2013 Jan-Feb;17(1):28-38; Black DM et al: Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007 May 3;356(18):1809-22; Bolland MJ et al: Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010 Jul 29;341:c3691; Conners WP 3rd, Morgentaler A: The evaluation and management of testosterone deficiency: the new frontier in urology and men’s health. Curr Urol Rep 2013 Dec;14(6):557-64; Das S, Crockett JC: Osteoporosis — a current view of pharmacological prevention and treatment. Drug Des Devel Ther 2013 May 31;7:435-48; Dawson-Hughes B: A revised clinician’s guide to the prevention and treatment of osteoporosis. J Clin Endocrinol Metab 2008 Jul;93(7):2463-5; Dawson-Hughes B et al: Implications of absolute fracture risk assessment for osteoporosis practice guidelines in the USA. Osteoporos Int 2008 Apr;19(4):449-58; Dobs AS: The role of accurate testosterone testing in the treatment and management of male hypogonadism. Steroids 2008 Dec 12;73(13):1305-10; Dobs AS, Morgentaler A: Does testosterone therapy increase the risk of prostate cancer? Endocr Pract 2008 Oct;14(7):904-11; Gentry J et al: Hypogonadism in primary care: the lowdown on low testosterone. South Med J 2013 Sep;106(9):492; Hiligsmann M et al: Cost-effectiveness of denosumab in the treatment of postmenopausal osteoporotic women. Expert Rev Pharmacoecon Outcomes Res 2013 Feb;13(1):19-28; Khalili H et al: Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study. BMJ 2012 Jan 30;344:e372; Khera M et al: Improved sexual function with testosterone replacement therapy in hypogonadal men: real-world data from the Testim Registry in the United States (TRiUS). J Sex Med 2011 Nov;8(11):3204-13; Kovac JR et al: Patient satisfaction with testosterone replacement therapies: the reasons behind the choices. J Sex Med 2013 Nov 6; Matsumoto AM: Testosterone administration in older men. Endocrinol Metab Clin North Am 2013 Jun;42(2):271-86; Miner MM, Sadovsky R: Evolving issues in male hypogonadism: evaluation, management, and related comorbidities. Cleve Clin J Med 2007 May;74 Suppl 3:S38-46; Morgan SL: Dietary supplements and medical foods for osteopenia and osteoporosis. J Clin Densitom 2013 Oct-Dec;16(4):394-401; Prentice RL et al: Health risks and benefits from calcium and vitamin D supplementation: Women’s Health Initiative clinical trial and cohort study. Osteoporos Int 2013 Feb;24(2):567-80; Saleh A et al: Bisphosphonate therapy and atypical fractures. Orthop Clin North Am 2013 Apr;44(2):137-51; Tella SH, Gallagher JC: Prevention and treatment of postmenopausal osteoporosis. J Steroid Biochem Mol Biol 2013 Oct 29. pii:S0960-0760(13)00182-9; Watts NB: Osteoporosis in men. Endocr Pract 2013 Sep-Oct;19(5):834-8.

Disclosures

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, members of the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Alton Reider spoke at Update in Internal Medicine: Evidence-Based Approaches to Common Medical Problems, held October 10-11, 2013, and presented by the University of Pittsburgh School of Medicine.  For more on upcoming CME events presented by the University of Pittsburgh School of Medicine, their web address is www.ccehs.upmc.com. The Audio-Digest Foundation thanks the speaker and the sponsor for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

Lecture ID:

IM611102

Qualifies for:

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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