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Amin Sabet, M.D.
04-02-2010
- Hypogonadism in a male refers to decreased spermatogenesis and/or testosterone action.
- Classified as primary (resulting from testicular disease) or secondary (resulting from pituitary or hypothalamic disease).
- Hypogonadism may be a cause of, but is to be distinguished from, erectile dysfunction.
- Total testosterone level that is 2.5 standard deviations below the mean in young adults or less than ~300 ng/dl.
- Clinical criteria are more ambiguous.
- In cross-sectional studies, between 20 - 64% of men with diabetes have hypogonadism; higher prevalence rates in the elderly (Dhindsa; Kalyani).
- Diabetes risk factor for hypogonadism through various mechanisms including: increased body weight; decreased sex hormone binding globulin (SHBG); suppression of gonadotrophin release or Leydig cell testosterone production; cytokine-mediated inhibition of testicular steroid production; and increased aromatase activity contributing to relative estrogen excess.
- Low testosterone levels independent risk factor for type 2 diabetes, even after adjusting for adiposity, possibly due to: androgen receptor polymorphisms; alterations in glucose transport; or reduced antioxidant effect (Stellato; Kalyani).
- Diagnose hypogonadism based on decreased sperm count and/or low testosterone levels relative to age-matched reference values (i.e. <300-400 mg/dl).
- Due to diurnal testosterone fluctuations, measure testosterone at 8 am in addition to FSH, LH.
- Total testosterone may not accurately reflect gonadal status in obese (low SHBG) and elderly patients (high SHBG); free and bioavailable testosterone levels should be checked if hypogonadism suspected.
- Free and bioavailable testosterone levels can be measured directly or calculated from total testosterone, albumin, and SHBG (online calculator available at http://www.issam.ch/freetesto.htm)
- In hypogonadal men, high LH/FSH indicates primary hypogonadism and normal or low FSH/LH indicates secondary hypogonadism.
- Primary hypogonadism causes: infection (i.e. mumps), trauma, chemotherapy, radiation exposure, cryptoorchidism, Klinefelter's syndrome.
- Secondary hypogonadism causes: hypopituitarism, hyperprolactinemia, hypothyroidism, hemochromatosis, long-term opioid use, obesity.
- Chronic systemic illnesses such as HIV, liver disease/cirrhosis, renal failure and diabetes may have mixed effects but are more likely to be associated with secondary hypogonadism (Kalyani).
- In primary hypogonadism, peripheral blood karyotype analysis should be performed to evaluate for Klinefelter syndrome (47 XXY).
- In secondary hypogonadism, measure serum prolactin, thyroxine, morning cortisol, iron saturation, and obtain pituitary MRI.
- Symptoms of postpubertal hypogonadism include sexual dysfunction, infertility, gynecomastia, reduced energy, depressed mood or diminished sense of well being, increased irritability, difficulty concentrating, hot flushes, decreased bone density, weakness, fatigue, anemia, decreased lean body mass and increased body fat.
- Eunuchoid proportions (lower > upper body segment and arm span more than 5 cm > height) indicate prepubertal onset of hypogonadism.
- Loss of male secondary sex characteristics such as body hair distribution and muscle mass may take years to occur after onset of hypogonadism.
- Small testicular size (normal >25 cc) on physical examination.
- Men should have both a low serum testosterone level and symptoms classically associated with hypogonadism before testosterone replacement therapy is offered.
- Primary treatment is testosterone therapy with goal of restoring testosterone levels to normal range and symptomatic improvement.
- Testosterone treatment contraindicated in presence of active prostate cancer or breast cancer and may worsen erythrocytosis, obstructive sleep apnea, severe lower urinary tract symptoms, or severe congestive heart failure.
- Transdermal testosterone is available as gel, patch, or buccal testosterone tablet.
- Testosterone patch: inital dose is 5 mg per day but may result in application site reactions.
- Testosterone 1% gel: initial dose is 5 gm (50 mg testosterone) per day and is usually preferred as first-line therapy since application site reactions are less.
- Testosterone enanthate and cypionate are administered intramuscularly. Initial dose 150-200 mg injected every two weeks; often preferred in children. Usually not preferred in adults since testosterone levels will have non-physiological peaks and troughs.
- Intramuscular testosterone therapy improves obesity and glycemic control in patients with diabetes (Kapoor).
- Monitor symptoms 3 months after initiating testosterone therapy and regularly thereafter.
- Monitor testosterone levels 2-3 months after initating testosterone therapy and every 6 months thereafter. If given IM, levels should be checked midway between injections.
- Perform digital rectal exam (DRE) and check PSA and hematocrit at baseline, 3 months after initiating testosterone therapy, and every 6-12 months thereafter.
- Obtain urology consultation if PSA > 4 ng/ml, if PSA increases by > 1.4 ng/ml within any 1-year period, PSA velocity > 0.4 ng/ml per year for > 2 years, or if abnormal findings on DRE.
- Stop therapy and assess for hypoxia and sleep apnea if hematocrit exceeds 54%.
- Consider also checking lipid panel and liver function tests.
- Measure bone mineral density after 1-2 years of testosterone therapy in hypogonadal men with osteoporosis.
- Diabetes more likely to be associated with secondary hypogonadism.
- Benefits of testosterone treatment may include not only improvement of hypogonadal symptoms, but also better glycemic control and reduced obesity in persons with diabetes.
- Commonly available free testosterone assay by direct RIA is unreliable and should not be used to diagnose hypogonadism.
- The most reliable and efficient approach we use is to start with total testosterone measurement. If this is normal, then hypogonadism can be excluded. If the total testosterone is low in a patient with obesity and/or diabetes, free testosterone is calculated from total testosterone, SHBG, and albumin (Rosner).
- Because testosterone levels fluctuate even in early morning, measurement should be repeated to confirm low levels on at least two occasions prior to making diagnosis of hypogonadism.
- Testosterone gel is preferred for treatment, avoiding the non-physiologic peaks and troughs of testosterone injection as well as application site reactions of testosterone patch, but care must be taken to avoid skin transfer to women and children.
- Bhasin S, Cunningham GR, Hayes FJ, et al.;
Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline.;
J Clin Endocrinol Metab;
2006; Vol.
91; pp.
1995-2010;
ISSN:
0021-972X;
PUBMED: 16720669
Rating:
Basis for recommendation
Comments:Endocrine Society practice guideline on treatment of hypogonadism
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