Katie S. Murray, DO
Tomas L. Griebling, MD, MPH, FACS
BASICS
DESCRIPTION
• Hypogonadism is a reduction in serum testosterone and other circulating androgens
– Primary hypogonadism: Arises directly from testicular causes
– Secondary hypogonadism is where changes occur in hypothalamic–pituitary–testicular axis
– Late-onset hypogonadism is a gradual reduction in serum testosterone levels in elderly men; often referred to as “andropause.”
EPIDEMIOLOGY
• Estimates suggest more than 4.5 million elderly American men may be affected
• 80% of men report moderate or severe scores consistent with hypogonadism on surveys (1)[B]
• Thought to be underreported and underdiagnosed in elderly males
RISK FACTORS
Decreases in serum testosterone occur naturally as part of the aging process
Genetics
• Attenuated action of androgen receptor (AR) may contribute
• Those with longer AR CAG repeat polymorphism are at higher risk of andropausal symptoms (2)[B]
PATHOPHYSIOLOGY
• Testosterone age-related declines vary by reported study:
– Testosterone declined approximately 100 ng/dL (3.5 nmol/L) from age 20–80 yr
– European Male Aging Study (EMAS) total testosterone (TT) fell 0.4% a year and the free testosterone fell 1.3% from age 40–79 yr
• As age increases, there is:
– Decreased number of Leydig cells within the testicle (site of testosterone production)
– Decreased testicular responsiveness to LH
– Dampening in the amplitude of circadian release of T
– Increased serum sex hormone binding globulin (SHBG)
binds T, therefore less bioavailable (functionally active) T
• Relationship with cardiovascular (CV) disease is thought to be multifactorial
– Nitric oxide (NO) is an important mediator in both CV health and erectile function
ASSOCIATED CONDITIONS
• Metabolic syndrome
• Diabetes mellitus
• Hypertension
• Tobacco abuse
• Sleep apnea
• Psychological disorders
• Social stress
GENERAL PREVENTION
None
DIAGNOSIS
HISTORY
• Patients often complain of:
– Frailty-decreased grip strength, diminished gait speed, easy fatigue and exhaustion, unintentional weight loss, and low levels for physical activity
– Decreased energy
– Decreased mentation
– Diminution in muscle mass and strength
– Decreased libido
– Erectile dysfunction
– Loss of morning erections
– Increased visceral fat
– Decrease in bone mineral density (osteoporosis and osteopenia)
– Sleep disturbances
– Depression
– Metabolic syndrome
– Poor glycemic control and diabetes mellitus
– Coronary/CV disease
PHYSICAL EXAM
• Overall energy, muscle mass, and disposition
• Psychological evaluation
– Screen for clinical depression
• Include complete GU exam
– Testis (size, consistency), digital rectal exam
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• TT: Diurnal variations so most accurate specimens are obtained in the morning (prior to 10:00 AM)
– General accepted values although there is no clear lab definition of hypogonadism
– <300 ng/dL with symptoms
– <200 ng/dL without symptoms
– FDA research trial definition: <300 ng/dL
• Free testosterone
– <50 pg/mL
• SHBG (sex hormone binding globulin)
– Increases with aging, which leaves a greater percentage of protein-bound testosterone and lower levels of circulating free testosterone
• Estradiol: Increased aromatization of testosterone to estradiol in adipose tissue
• If abnormal TT levels, then check LH and prolactin
• Blood glucose to screen for diabetes mellitus
• PSA for prostate cancer screening
• Monitoring while on testosterone replacement therapy (TRT)
– CBC to monitor hematocrit (risk of polycythemia)
– PSA
– Liver function tests
Imaging
Bone density scan to evaluate for osteopenia or osteoporosis
Diagnostic Procedures/Surgery
Prostate biopsy if PSA and DRE are suspicious for prostate cancer
Pathologic Findings
N/A
DIFFERENTIAL DIAGNOSIS
• Acute critical illness (surgery, head trauma)
• Age-related decline (“Andropause”)
• Alcoholism
• Chronic illness (liver failure, chronic renal failure, hypertension, hypothyroidism, diabetes, sleep apnea, obesity, anorexia nervosa, depression, HIV)
• Hematologic (sickle cell disease, thalassemia)
• Hemochromatosis of the pituitary, Leydig cells
• Hypopituitarism (hypothalamic/pituitary)
• Kallmann syndrome (congenital absence of GnRH)
• Klinefelter syndrome
• Medications: LHRH analogs/antagonists, glucocorticoids, androgens, estrogens, progestins (eg, megestrol), chronic opioids, marijuana (controversial)
• Noonan syndrome
• Pituitary infections, infiltration, trauma, radiation (decreased LH/FSH production)
• Pituitary tumors, macroadenomas, hyperprolactinemia
• Prader–Willi syndrome
• Sertoli-cell-only syndrome
• Testicular failure (primary): Congenital or acquired anorchia, cryptorchidism, mumps orchitis, radiation therapy, chemotherapy
• Testicular tumors
TREATMENT
GENERAL MEASURES
• Can treat ED with phosphodiesterase-5 inhibitors if no contraindications
– Avanafil
– Sildenafil
– Tadalafil
– Vardenafil
– Start at lowest dose and titrate up for efficacy
MEDICATION
First Line
• TRT (3)[B]
– Intramuscular, transdermal (patches and gels), and buccal preparations. See Section I “Testosterone Replacement Therapy, General Principles” for specifics on TRT agents
– Selection is dependent on patient/physician preference and feasibility
– Considerations in the older male: The American Geriatrics Society (AGS) lists testosterone in the Beers Criteria as a medication to generally avoid in older adults because of potential for cardiac problems and men with personal history of prostate cancer (4)[A]
– The choice of TRT should be individualized on specific clinical needs
– Absolute contraindications: Personal history of breast cancer or untreated prostate cancer
– Relative contraindications: Polycythemia, BPH causing urinary retention, treated prostate cancer
Second Line
N/A
SURGERY/OTHER PROCEDURES
Men with primary erectile dysfunction complaints can discuss surgical placement of penile prostheses, use of vacuum erection devices, or vasoactive intracavernosal injection therapy
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
N/A
Complementary & Alternative Therapies
• Increased weight-bearing exercise
• Diet and exercise
• Weight loss
• Phytotherapies: Limited research on safety and efficacy of herbal medications
– Limited data on ability of any OTC supplement to influence T levels
ONGOING CARE
PROGNOSIS
• TRT is associated with improved responses in many areas
– Quality of life
– Mood and affect
– Sexual function and libido
– Cognitive function
– Glycemic control
COMPLICATIONS
• Prostate cancer diagnosis or progression of disease
• Polycythemia
– Potential for cardiac and cerebral vascular events
FOLLOW-UP
Patient Monitoring
• Hemoglobin and hematocrit
• Bone mineral density
• DRE and PSA for prostate cancer screening
• Continued monitoring of testosterone levels
• Overall men’s health issues
– Blood glucose
– Serum lipids
– Overall cardiovascular health
Patient Resources
Urology Care Foundation AUA www.urologyhealth.org/urology/index.cfm?article=132
REFERENCES
1. Trinick TR, Feneley MR, Welford, et al. International web survey shows high prevalence of symptomatic testosterone deficiency in men. Aging Male. 2011;14:10–15.
2. Liu CC, Lee YC, Wang CJ, et al. The impact of androgen receptor CAG repeat polymorphism on andropausal symptoms in different serum testosterone levels. J Sex Med. 2012;9:2429–2437
3. Bhattacharya RK, Khera M, Blick G, et al. Testosterone replacement therapy among elderly males: The Testim Registry in the US (TRiUS). Clin Interv Aging. 2012;7:321–330.
4. American Geriatric Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2012;15:22–27.
ADDITIONAL READING
• 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 Metabol. 2010;95:2536–2539.
• Petak SM, Nankin HR, Spark RF, et al. American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients–2002 Update. Endocr Pract. 2002;8:440–456.
See Also (Topic, Algorithm, Media)
• Beers Criterion
• Erectile Dysfunction/Impotence, General Considerations
• Hypogonadism, Society Definitions
• Testis, Normal Size
• Testosterone (Free and Total) Lab Testing
• Testosterone Replacement Following Localized Prostate Cancer Therapy
• Testosterone Replacement Therapy, General Principles
• Testosterone, Decreased (Hypogonadism)
CODES
ICD9
• 253.4 Other anterior pituitary disorders
• 257.2 Other testicular hypofunction
ICD10
• E23.0 Hypopituitarism
• E29.1 Testicular hypofunction
CLINICAL/SURGICAL PEARLS
Treatment is based upon symptomatology more than lab values.