I. Pathophysiology--Can be due to primary gonadal failure or secondary to pituitary failure (hypogonadotropic hypogonadism; e.g. b/c of nonfunctioning pituitary tumors)

  1. Primary gonadal failure
    1. Kallman syndrome
    2. Klinefelter syndrome
    3. Mutations affecting gonadotropins or androgen synthesis
    4. Testicular tissue damage (orchitis, trauma, orchiectomy, torsion)
    5. Chronic renal or hepatic disease
    6. HIV infection
    7. Cryptorchidism
    8. Alcoholism
    9. Effects of chemotherapy or radiation
    10. Myotonic dystrophy
    11. Medications (e.g. ketoconazole)
  2. Hypogonadotropic hypogonadism (low FSH and LH)
    1. Usually with pan-hypopituitarim (i.e. with decreases in TSH and ACTH) more common
    2. Can occur as a result of hemochromatosis, with excessive pituitary Fe deposition causing reduced gonadotropin secretion (often without altering other pituitary hormone levels)
    3. Hyperprolactinemia can suppress gonadotropin secrection
    4. Glucocorticoids
    5. Tumors, infection, etc. affecting pituitary

II. Clinical features

  1. Erectile Dysfunction--However, Occurs without erectile dysfunction in as many as 25% of males over 50 (J. Clin. Endo. Metab. 1:963, 1990
  2. Osteoporosis
  3. Decreased libido
  4. May be associated with  loss of energy and Depression
  5. Decreases in lean body mass
  6. Vasomotor symptoms
  7. Reduced quality of life
  8. May increase risk of Alzheimer's Disease--See link for details

III. Diagnosis

  1. Start with early-morning serum total testosterone
  2.  Free testosterone level corrects for abnormalities in sex hormone-binding globulin levels (SHBG may be altered with hypothyroidism, obesity, chronic illness, diabetes mellitus, and certain medications)
  3. If hypotestosteronemia is confirmed with > 1 measurement, check FSH and LH to differentiate primary hypogonadism (levels will be high) vs. hypogonadotropic hypogonadism (levels will be low)

IV. Testosterone replacement

  1. Risks
    1. Accelerated growth of androgen-sensitive cancers including Prostate Cancer-Contraindicated in pts with known prostate Ca
    2. Worsening of Benign Prostatic Hyperplasia
    3. Concern has been raised about effects on serum lipids but no diff. from placebo seen in a 3y randomized trial of transderm testosterone replacement in 96 hypotestosteronemic men (Am. J. Med. 111:255, 2001--JW)
    4. Can cause erythrocytosis in older men; avoid in patients with erythrocytosis
    5. Other potential side effects
      1. Acne
      2. Weight gain
      3. Worsening of lipid levels
      4. Gynecomastia
      5. BP elevations
      6. Mood fluctuations and aggressive behavior
      7. Excessive body hair growth
  2. Benefits
    1. Improved bone density
      1. In a randomized trial in 70 men with serum testosterone < 350ng/dL randomized to testosterone 200mg IM Q2wks, testosterone + oral finasteride, or placebo, over 3y f/u, bone mineral density sig. increased from baseline in both active-tx groups but not in placebo group (don't have reference!)
      2. In a36mo study in 70 men  >65yo with serum testosterone < 12.1nmol/L randomized to testosterone enanthate 200mg IM Q2wks + oral placebo, testoseterone with finasteride 5mg/d, or double placebo, both testosterone regimens were ass'd with sig. increases in bone mineral density; the testosterone-alone group, but not the combined testosterone-finasteride group, had sig. increases in PSA.  (J. Clin. Endocrin. Metab ol. 89:503, 2004--abst)
    2. Improved sexual function
      1. Only 50% of hypogonadal men with ED will have improved erections with testosterone; tends to have more effect on libido
  3. Consider stopping treatment if symptomatic improvement not attained within 3-6 months of starting therapy, unless indicated for bone sensity
  4. Lab monitoring Consider PSA & LFT's before starting & periodically during therapy
  5. IM testosterone enanthate or cypionate
    1. Start with 200-300mg  q 3-4wks;
    2. Check serum testosterone levels 1 and 2wks post-injection; titrate dose and frequency response
  6. Transdermal patches (Androderm, Testoderm)
  1. Testoderm is worn on scrotum
  2. Dose is 2.5-6mg/d; check serum levels 2h after applying patch
  3. Difficult to keep in place; 8% get skin irritation
  4. Claimed to achieve more "physiologic" serum levels; does produce mich higher ratio of dihydrotestosterone to testosterone than seen in eugonadal men; the significance of this is unknown
  1. Transdermal Gel
    1. May transmit testosterone to others by skin-to-skin contact
    2. Titrate dose to serum testosterone levels
    3. Specific brand formulations
      1. Androgel 1%--Start at 5g QD (also available as 1.62%)
      2. Testim 1%--Start at 5g QD
  2. Buccal tablet--"Striant"--Start at 30mg BID
  3. Oral androgens are generally avoided because first-pass metabolism causes high liver toxicity for most formulations (testosterone undecanoate the least)
(Sources include Core Content Review in Family Medicine, 2012)