> Table of Contents > Testosterone Deficiency
Testosterone Deficiency
Michael Lao, MD
Gregory Murphy, MD
Stanton C. Honig, MD
image BASICS
DESCRIPTION
  • Testosterone (T) is a critical anabolic hormone involved in various key metabolic pathways.
  • It is the principle circulating androgen in males.
  • Critical in modulating bodily processes of the cardiovascular, reproductive, hematologic, central nervous, and musculoskeletal systems
  • Testosterone deficiency (TD), or hypogonadism, is characterized by low levels of T, often in addition with signs and symptoms attributed to low T levels.
  • No universally accepted threshold of T concentration to distinguish eugonadal from hypogonadal men, but the FDA definition is T <300 ng/dL.
  • Clinically, TD is divided into primary and secondary.
  • T levels can be affected by medical conditions that influence the hypothalamic-pituitary-testis axis, age, and medical comorbidities.
  • T levels correlates with overall health and may be associated with sexual function
  • T levels decline by 1% per year after age 40.
  • Special consideration is needed for men with low T who desire future fertility.
  • Synonym(s): hypogonadism; hypoandrogenism; androgen deficiency; and low T
EPIDEMIOLOGY
Incidence
  • Overall incidence increases with age
  • Symptomatic TD in men in United States ages 30 to 79 years is 5.6%
  • 481,000 new cases in the United States in men 40 to 69 years
Prevalence
  • Estimates of TD vary widely, but typically 20% of men over 60, 30% over 70, and 50% over 80 years of age.
  • 2 to 4 million men in United States
ETIOLOGY AND PATHOPHYSIOLOGY
  • Normal hypothalamic-pituitary-testis axis:
    • Hypothalamus produces GnRH, which stimulates pituitary to produce follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
    • LH stimulates the leydig cells to produce T; responsible for 90% of the body's T.
    • T inhibits LH and GnRH through negative feedback at level of hypothalamus and pituitary.
  • Primary hypogonadism: Testes produces insufficient amount of T, FSH/LH levels are elevated.
  • Secondary hypogonadism: low T from inadequate production of LH
  • Mixed hypogonadism: low to normal LH in combination with reduced production of T
  • Normal aging process
  • Congenital syndromes: cryptorchidism, Klinefelter
  • Acquired: cancer, trauma, orchiectomy, prior anabolic steroid abuse
  • Infectious: mumps orchitis, HIV, tuberculosis
  • Systemic: Cushing syndrome, hemochromatosis, autoimmune, severe illness (e.g., renal disease, cirrhosis), metabolic syndrome, obesity, obstructive sleep apnea, hypogonadotropic hypogonadism
  • Drugs and medications: LHRH agonists (leuprolide), corticosteroids, ethanol, ketoconazole, spironolactone, marijuana, opioids, cimetidine
  • Elevated prolactin: prolactinoma, dopamine antagonists (e.g., neuroleptics and metoclopramide)
Genetics
  • Usually normal
  • Klinefelter: XXY karyotype
  • Kallmann: abnormal GnRH secretion due to abnormal hypothalamus development
RISK FACTORS
  • Obesity, diabetes, COPD, depression, hypothyroid, malnutrition, alcohol, stress
  • Chronic infections or inflammatory diseases
  • Medications that affect T production or metabolism
  • Undescended testicles
  • Trauma, testicular radiation, chemotherapy, disorders of the pituitary and/or hypothalamus
GENERAL PREVENTION
General health maintenance and treatment of obesity
COMMONLY ASSOCIATED CONDITIONS
  • Infertility, erectile dysfunction, low libido
  • Poorer health outcomes
  • Osteopenia/osteoporosis and fractures
  • Diabetes and insulin resistance, metabolic syndrome
  • Increased body weight, adiposity
  • Sleep disturbance and depressed mood, poor concentration, irritability
image DIAGNOSIS
PHYSICAL EXAM
  • Infancy: ambiguous genitalia
  • Puberty
    • Impaired growth of penis, testicles
    • Lack of secondary male characteristics
    • Gynecomastia, eunuchoid habitus
  • Adulthood
    • Decreased muscular development, visceral fat distribution; body habitus changes to suggest corticosteroid excess
    • Presence of gynecomastia
    • Skin changes to suggest hemochromatosis
    • Eunuchoid habitus
  • Genitourinary exam
    • Small and/or soft testicles
DIFFERENTIAL DIAGNOSIS
  • Delayed puberty
  • Obesity
  • Normal aging
  • Prior anabolic steroid abuse
DIAGNOSTIC TESTS & INTERPRETATION
  • T levels vary widely, they are subject to diurnal, seasonal, and age-related variations. There are multiple assays, each with unique characteristics. Measurement should be obtained between 6 to 10 AM. Confirmation with a second measurement may be necessary. Whether total T or free T most closely correlates with symptomatic deficiency is unclear. Free T with total T is generally preferred. Measurements should not be obtained during acute or subacute illness. T circulates in blood primary bound to SHBG or to albumin. Only 2-3% of total T is found free. Free and albumin-bound T is considered bioavailable. Laboratory findings must be interpreted in the appropriate clinical setting. Bioavailable T is considered most important, but assays are not readily available and calculated bioavailable T is not reliable.
  • Lower limit of normal in most reference laboratories for total testosterone is 280 to 300 ng/dL (9.8 to 10.4 nmol/L). The lower limit of normal for free testosterone is 5 to 9 pg/mL (0.17 to 0.31 nmol/L).
Initial Tests (lab, imaging)
  • In symptomatic individuals, morning T level is the initial test. Morning timing is more important for younger men in whom there is more diurnal variation. If initial morning testosterone is low and confirmed on repeat test, further evaluation is appropriate (2)[A].
  • Endocrine evaluation should include LH and FSH to differentiate between primary versus secondary hypogonadism.
  • If primary hypogonadism of unknown origin, consider obtaining karyotype (e.g., Klinefelter) if severe testis atrophy exists.
  • If secondary hypogonadism, evaluation may consist of prolactin, iron saturation, pituitary function testing, and/or MRI of pituitary.
  • Imaging is not helpful in the initial diagnosis of TD.
  • No evidence to support screening for TD in the general population
Follow-Up Tests & Special Considerations
  • Routine blood work to measure T response to interventions
  • Dual-emission x-ray absorptiometry (DEXA) to measure bone mineral density in men with severe TD or fracture from minimal trauma.
  • Pituitary MRI: if there is elevation of prolactin more than twice the upper limit of normal or LH/FSH below normal range
image TREATMENT
T replacement is recommended for symptomatic men (e.g., low libido and/or erectile dysfunction, low energy level, constitutional symptoms, etc.) with low T levels ≤300 ng/dL obtained in the morning. Not recommended for older men with low T levels in absence of signs or symptoms.
GENERAL MEASURES
  • Confirm suspicion.
  • Obtain hematocrit, prostate-specific antigen (PSA) in men > 40 years, prolactin, LH/FSH, SHBG, estradiol.
  • Baseline physical exam including digital rectal exam, and International Prostate Symptom Score (IPSS)
  • Correction of underlying cause
  • Is future fertility an issue? Different treatment strategies are used in men of reproductive age and/or interest.
  • P.1025

  • Current evidence fails to demonstrate that higher serum T is associated with greater prostate cancer risk.
  • Safety of T therapy in prostate cancer is still uncertain and contraindicated in package insert.
  • 2010 Endocrine Guidelines: Patients with organconfined prostate cancer who have undergone radical prostatectomy and have been disease free for ≥2 years after surgery with undetectable PSA may be considered for T replacement on an individualized basis. Lack of data from randomized trials precludes a general recommendation.
  • T therapy should not be used in men with hematocrit >50%, untreated obstructive sleep apnea, and severe lower urinary tract symptoms with an IPSS >19 (3)[A].
  • T therapy is not recommended for: mood or strength improvement in otherwise healthy men, or asymptomatic men with low T measurements (3)[A].
  • Carefully weigh risks and benefits in men at elevated cardiovascular risk (3,4)[A].
  • Clinicians can consider starting short-term T therapy as an adjunctive in men with HIV and low T to promote weight maintenance and gains in lean body mass and strength.
MEDICATION
  • Oral therapy is not recommended due to significant hepatotoxicity.
  • The FDA has cautioned that testosterone is approved for men with confirmed low testosterone by laboratory testing and caused by certain medical conditions, NOT just due to aging.
  • Despite prior data showing no clear association between testosterone replacement therapy (TRT) and CV disease, there have been several recent papers suggesting that TRT use puts patients at an increased risk for CV disease. These papers have been criticized widely for being flawed due to comparison of unequal groups, short and inaccurate endpoints, flawed laboratory testing, erroneous exclusion criteria, and atypical statistical analysis. Despite this, an FDA panel concluded that there is a possible increased CV risk associated with testosterone use.
  • Testosterone replacement therapy (FDA approved)
    • Topical gels/solutions
      • Multiple FDA-approved formulations
      • Most frequently prescribed in United States
      • Mimics normal daily circadian rhythm
      • Good absorption, but 15-20% are nonresponders
      • Transfer concern to children and women
      • Dosage adjustments to obtain optimal results
      • Gel application: arms, back, axilla, and groin
    • Testosterone pellets (Testopel)
      • Minor office procedure with mild discomfort
      • Long-acting formulation, 3 to 4 months
      • 1-2% risk of infection or pellet extrusion
    • Transdermal patch (Androderm)
      • Achieves less robust levels
      • Convenient over gels, no risk of transference
      • High incidence of skin irritation
    • Testosterone cypionate and enanthate (short acting)
      • Injectable (IM), inexpensive
      • Inconvenient: injections every 1 to 3 weeks
      • Starting dose: 100 mg/week, or 200 mg/2 weeks
      • Roller coast effect: levels rise and fall
    • Testosterone undecanoate (long acting)
      • Injectable, expensive, convenient
      • Small risk of oil embolism, needs observation in office for 30 minutes postinjection
      • Given approximately every 8 to 12 weeks
    • Buccal application (Striant)
      • Adheres to gum line, irritation in 16.3%
      • Poor compliance, every 12 hours application
    • Nasal gel (Natesto)
      • Levels overdosing schedule are variable.
      • TID dosing, nasal irritation
  • OFF LABEL TREATMENT
    • Human chorionic gonadotropin (hCG)
      • Structure similar to LH, mimicks its actions
      • Frequent, 3 times per week starting at 1,500 IU SC
      • Poor compliance
      • Maintenance of testicular volume and fertility
      • Used in men wanting to preserve fertility
    • Clomiphene citrate: oral agent
      • Increases T by interfering with negative feedback, resulting in increased LH and FSH
      • Starting dose of 25 mg daily 3 to 7 times weekly
      • Used in men wanting to preserve fertility
    • Aromatase inhibitors (Arimidex): oral agent
      • Blocks conversion of T to estradiol
      • Does not negatively impact spermatogenesis and testicular volume
      • Utilized in cases of low T/estradiol ratio
ISSUES FOR REFERRAL
  • Elevated PSA and/or abnormal prostate exam should be referred to urology.
  • Worsening symptoms of BPH or increasing IPSS
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • Necessary to monitor effectiveness of therapy as well as for adverse effects: Initially 3 to 6 months after treatment initiation and then annually
  • Measure hematocrit at baseline, at 3 to 6 months, and then annually. If hematocrit >54% or symptomatic, stop therapy until hematocrit decreases to a safe level. Treatment includes phlebotomy, blood donation, or adjustment of dose.
  • Evaluate patient for hypoxia or sleep apnea.
  • Monitor bone mineral density after 1 to 2 years of therapy in these men with osteoporosis or low trauma fracture.
  • Changes in voiding symptoms
  • Prostate exam done regularly every 6 to 12 months.
  • Refer to urology when increase in PSA >0.7 ng/mL within any 12-month period of T treatment or detection of prostatic abnormality on prostate exam.
DIET
Healthy diet and weight reduction if obese
PATIENT EDUCATION
  • TD is chronic and likely to need lifelong therapy.
  • T replacement comes with many risks, and it is very important to regularly monitor outcomes.
  • Women and children must not be allowed to come in contact with T-replacement gel products.
PROGNOSIS
  • Sustained reversal of symptoms can be achieved when serum levels of T fall in the normal range.
  • Adverse health effects seen in many with chronically low levels of T
REFERENCES
1. Conners WP III, Morgentaler A. The evaluation and management of testosterone deficiency: the new frontier in urology and men's health. Curr Urol Rep. 2013;14(6):557-564.
2. Paduch DA, Brannigan RE, Fuchs EF, et al. The laboratory diagnosis of testosterone deficiency. Urology. 2014;83(5):980-988.
3. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559.
4. Jenkins LC, Mulhall JP. Editor's comment—how dangerous is testosterone supplementation? Int Braz J Urol. 2015;41(2):195-198.
Additional Reading
&NA;
  • Buvat J, Maggi M, Guay A, et al. Testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment. J Sex Med. 2013;10(1):245-284.
  • Vigen R, O'Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17): 1829-1836.
Codes
&NA;
ICD10
  • E29.1 Testicular hypofunction
  • E89.5 Postprocedural testicular hypofunction
Clinical Pearls
&NA;
  • Testosterone deficiency is common and prevalence increases with age.
  • Testosterone deficiency can have negative adverse impact on many bodily systems.
  • Symptomatic men with sexual dysfunction, obesity, and metabolic diseases should be tested for testosterone deficiency and treated.
  • Initial test of choice is a morning total and free testosterone; if low, repeat measurements.
  • Testosterone replacement therapy in the appropriately selected population can increase lean mass, reduce fat mass, increase bone density, improve libido, and improved erections.