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Testosterone Deficiency

Stanton C. Honig, MD
Dylan Buller, MD

BASICS

DESCRIPTION

  • Testosterone (T) is the principal circulating androgen in males.

  • Testosterone deficiency (TD) is characterized by low levels of T plus associated signs and symptoms.

  • No universally accepted threshold of T to distinguish eugonadal from hypogonadal men, but the FDA defines TD for regulatory purposes.

  • T levels correlate with overall health and may be associated with sexual dysfunction.

  • Synonyms: hypogonadism, hypoandrogenism, androgen deficiency

EPIDEMIOLOGY

  • Incidence increases with age.

  • T levels decline by ~1% per year after age 40.

  • Prevalence:

    • 20% of men >60 years

    • 30% >70 years

    • 50% >80 years

  • Symptomatic TD in US (40-69 yrs): 6–12.3%

  • 2.4 million men in US ages 40–69 years

ETIOLOGY AND PATHOPHYSIOLOGY

  • Hypothalamus produces GnRH → stimulates pituitary to produce FSH and LH.

  • LH stimulates Leydig cells (90% of body T) to produce T.

  • Primary hypogonadism: Testes produce insufficient T.

  • Secondary hypogonadism: Low T from inadequate LH.

  • Congenital syndromes: cryptorchidism, Klinefelter (XXY), Kallmann (abnormal GnRH secretion)

  • Acquired: cancer, trauma, orchiectomy, steroids

  • Infectious: mumps orchitis, HIV, TB

  • Systemic: Cushing syndrome, hemochromatosis, autoimmune, severe illness (renal/liver disease), metabolic syndrome, obesity, OSA

  • Medications/drugs: LHRH agonists, corticosteroids, ethanol, marijuana, opioids, SSRIs

  • Elevated prolactin: prolactinoma, dopamine antagonists (neuroleptics, metoclopramide)

  • Genetics:

    • Klinefelter syndrome: XXY

    • Kallmann syndrome: abnormal hypothalamic development

RISK FACTORS

  • Obesity, diabetes, COPD, depression, thyroid disorders, malnutrition, alcohol, stress

  • Chronic infections

  • Undescended testicles, varicocele

  • Trauma, cancer, testicular radiation, chemotherapy

  • Disorders of pituitary/hypothalamus

GENERAL PREVENTION

  • General health maintenance

  • Treatment of obesity

COMMONLY ASSOCIATED CONDITIONS

  • Infertility, erectile dysfunction, low libido

  • Osteopenia/osteoporosis

  • Diabetes, insulin resistance, metabolic syndrome, adiposity

  • Depressed mood, poor concentration, irritability

DIAGNOSIS

HISTORY

  • Congenital/developmental abnormalities

  • Infertility, loss of libido, erectile dysfunction

  • Depression, fatigue

  • Increased body fat, diabetes

  • Bone fractures (minor trauma)

  • Testicular trauma, infection, radio-/chemotherapy

  • Decrease in testicle size/consistency

  • Headaches/vision changes

  • Medications, narcotic use

PHYSICAL EXAM

  • Infancy: ambiguous genitalia

  • Puberty: impaired penis/testicle growth, lack of secondary male characteristics, gynecomastia, eunuchoid habitus

  • Adulthood: decreased muscular development, visceral fat, gynecomastia, small/soft testicles

  • Digital rectal exam and IPSS (International Prostate Symptom Score)

DIFFERENTIAL DIAGNOSIS

  • Delayed puberty

  • Obesity, depression, chronic illness, hypothyroidism

  • Normal aging

  • Prior anabolic steroid abuse

DIAGNOSTIC TESTS & INTERPRETATION

  • T levels vary: diurnal, seasonal, age-related

  • Measurement: between 6–10 a.m.

  • Repeat as needed.

  • Free T with total T may be preferred.

  • No acute illness during testing.

  • T circulates: mostly bound to SHBG/albumin; only 2–3% free (bioavailable = free + albumin-bound)

  • Initial Tests:

    • Morning T is initial test.

    • If low, repeat; if still low, LH and FSH

    • Estradiol, prolactin (if LH low or breast symptoms/gynecomastia)

    • Karyotype if severe atrophy (Klinefelter)

    • MRI/pituitary function if secondary hypogonadism

  • Follow-up:

    • Hemoglobin/hematocrit (risk of polycythemia)

    • PSA

    • Estradiol (breast symptoms/gynecomastia)

    • DEXA (severe TD/fracture)

    • MRI if prolactin >2x normal or LH/FSH low

TREATMENT

  • Testosterone therapy (TT) for symptomatic men (low libido/ED, low energy, constitutional symptoms) with morning T ≤300 ng/dL;

    • NOT recommended for older men with low T without symptoms

  • TT may improve anemia, bone density, strength; NOT shown to improve cognition/memory

  • Discuss fertility impact before exogenous T

  • Prostate cancer: Safety uncertain; contraindicated

    • AUA guidelines: history of prostate CA—insufficient evidence, caution

    • Endocrine guidelines: organ-confined prostate CA, disease-free ≥2y, undetectable PSA—TT may be considered individually

    • Avoid TT if PSA >4, or >3 + increased risk (African Americans, family history)

    • TT contraindicated: metastatic prostate CA, breast CA, Hct >54%, untreated OSA, uncontrolled CHF, severe LUTS (IPSS >19)

  • No TT for mood/strength improvement in healthy/asymptomatic men with low T

  • CV risk:

    • TD is CV risk factor

    • TT does not increase CV events even in high-risk men

  • Consider short-term TT in HIV+ men with low T for weight/lean mass

  • Oral methyltestosterone not recommended (hepatotoxicity)

  • Oral testosterone undecanoate (Jatenzo) FDA approved 2019 (BP warning)

  • Topical gels/solutions:

    • Mimic circadian rhythm

    • Good absorption, 15–20% nonresponders

  • Pellets (Testopel): 3–4 months duration, 1–2% infection/extrusion risk

  • Transdermal patch (Androderm): less robust levels, high skin irritation

  • Enanthate (Xyosted) SC weekly: warning for BP increase

  • Cypionate (IM): 100 mg/week or 200 mg/2w

  • Undecanoate (IM q8–12w): risk of oil embolism

  • Buccal (Striant) BID: gum irritation

  • Nasal gel (Natesto) TID: nasal irritation, may protect fertility

  • Titration required to determine dose

  • Avoid contact with females/children with gels

  • No TT for 3–6 months after acute CV event

  • Monitor for polycythemia, PSA, side effects

ISSUES FOR REFERRAL

  • PSA elevation, abnormal prostate, worsening BPH (IPSS >19), refractory symptoms: Refer to urology

ONGOING CARE

FOLLOW-UP

  • Monitor 3–6 months after starting TT, then every 6–12 months

  • Adjust dose for middle tertile of reference

  • Measure hematocrit: baseline, 3–6 months, annually

  • Stop TT after 3–6 months if no symptomatic improvement

  • Bone density after 1–2 years if osteoporosis

  • Prostate exam every 6–12 months

DIET

  • Lifestyle/weight loss may improve T levels without replacement

PATIENT EDUCATION

  • TD can be chronic; may need lifelong therapy

  • TT risks: Regular monitoring is crucial

  • Women/children must not contact gels

PROGNOSIS

  • TT may improve: metabolic function (HbA1c, glucose, cholesterol, fat), bone density, anemia

  • Not proven to improve cognition/memory in elderly

COMPLICATIONS

  • Decreased testicular volume, azoospermia (40% on TT), infertility

  • Mood/libido fluctuations

  • Gynecomastia, breast cancer growth

  • Acne, oily skin

  • Erythrocytosis (increased hematocrit)

  • Sleep apnea exacerbation

  • Hepatotoxicity (oral)

  • Possible prostate enlargement/worsening BPH

REFERENCES

  1. Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency: AUA guideline. J Urol. 2018;200(2):423-432.

  2. Debruyne FMJ, Behre HM, Roehrborn CG, et al. Testosterone treatment is not associated with increased risk of prostate cancer or worsening of lower urinary tract symptoms: prostate health outcomes in the Registry of Hypogonadism in Men. BJU Int. 2017;119(2):216-224.

  3. Linco... testosterone-replacement therapy. N Engl J Med. 2023;389(2):107-117.

Codes:

  • ICD10: E29.1 Testicular hypofunction, E89.5 Postprocedural testicular hypofunction

Clinical Pearls

  • TD is common, increases with age

  • Test for TD in men with sexual dysfunction, obesity, unexplained anemia, bone density loss, chronic steroid/narcotic use, metabolic disease

  • Morning total and free T: test of choice; repeat if low

  • TT can increase lean mass, reduce fat mass, increase bone density, improve libido, anemia, and erections

  • Not shown to improve cognition/memory in elderly

  • Lifestyle changes (diet/exercise) may restore T levels

End of note