Robert L. Segal, MD, FRCS(C)
Arthur L. Burnett, II, MD, MBA, FACS
BASICS
DESCRIPTION
• Hypogonadism is the clinical syndrome associated with low serum testosterone (T)
– Can occur in early age (early onset), although most commonly seen in aging males
– Late-onset male hypogonadism may also be referred to as andropause, androgen deficiency in the aging male, or androgen deficiency syndrome
EPIDEMIOLOGY
Incidence
N/A
Prevalence
• 2–4 million men in US
• Hypogonadism increases with age
– Overall 5.6–38.7% men are affected, depending on study
– 6th decade: 12%; 7th: 19%; 8th: 29%; 9th: 49%
RISK FACTORS
• Medical comorbidities (chronic liver disease, chronic renal failure/hemodialysis, HIV/AIDS, hyperthyroidism, obesity)
• Medication (GnRH agonists/antagonists, androgen antagonists, estrogen, opiates, ketoconazole, amiodarone, thiazide diuretics, cimetidine)
• Low protein diet
Genetics
N/A
PATHOPHYSIOLOGY
• As age increases, there is:
– Decreased number of Leydig cells within the testicle (site of T 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
ASSOCIATED CONDITIONS
• Metabolic syndrome (obesity, hypertension, dyslipidemia)
• Impaired fasting glucose/insulin resistance/diabetes mellitus type II (DMII)
• Asthma/chronic obstructive pulmonary disease/obstructive sleep apnea (OSA)
• Osteoporosis
GENERAL PREVENTION
N/A
DIAGNOSIS
HISTORY
• Low energy level/daytime sleepiness (2)[B]
• Decreased sexual interest/libido (2)[A]
• Erectile dysfunction (ED)/absence of spontaneous erections/delayed ejaculation (2)[A]
• Diminished mood/memory/concentration
• Hot flushes/sweats
• Loss of muscle mass/visceral obesity
• Visual field defects
• Several validated questionnaires to screen for T deficiency have been developed, but are unreliable with low specificity (1)[C]
PHYSICAL EXAM
• May not be contributory (2)[B]
• Small testicular size/soft consistency (2)[B]
• Hair distribution and pattern (2)[B]
• Gynecomastia (2)[B]
• Digital rectal exam (DRE) to rule out palpable prostate abnormality
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Total serum T (best before 11:00 am) (1)[A]
• Free T
• Bioavailable T
– No universally accepted lower limit of normal serum T
– It is generally agreed that serum T >12 nmol/L (3.5 ng/mL, 350 ng/dL) does not usually need replacement (2)[A]
– If T<8 nmol/L (2.3 ng/mL, 230 ng/dL) replacement is typically beneficial (2) [A]
• FDA research trial definition: Hypogonadism is total T levels of ≤300 ng/dL
• Serum albumin
• SHBG
• If secondary hypogonadism is suspected:
– Serum prolactin; Serum gonadotropins (LH); thyroid function
Imaging
• Cranial imaging (MRI, CT) if prolactinoma suspected
• Dexa scan for the assessment of bone mineral density if at risk for osteopenia/osteoporosis (1)[B]
Diagnostic Procedures/Surgery
N/A
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, Klinefelter, or Noonan syndrome
• Medications: LHRH analogues/antagonists, glucocorticoids, androgens, estrogens, progestins (eg, megestrol), chronic opioids, marijuana (controversial)
• Pituitary infections, infiltration, trauma, radiation (decreased LH/FSH production)
• Pituitary tumors, macroadenomas, hyperprolactinemia
• Syndromes Prader–Willi and Sertoli only
• Testicular failure (primary): Congenital or acquired anorchia, cryptorchidism, mumps orchitis, radiation therapy, chemotherapy
• Testicular tumors
TREATMENT
GENERAL MEASURES
• Treatment is warranted for men with clinical symptoms associated with objective biochemical findings of low T (2)[C]
– In the context of significant symptoms and normal or borderline T levels, a trial of TRT is acceptable with appropriate follow-up to ensure improvement in symptoms (2)[C]. If no improvement is noted, further workup to delineate cause is warranted
• In the presence of visceral obesity, weight loss through regular exercise and low-caloric intake is recommended (2)[A]
• Appropriate glycemic, blood pressure, and lipid management is recommended
• TRT contraindications include:
– Known prostate cancer (absolute)
– Known breast cancer (absolute)
– Unexplained prostate-specific antigen (PSA) elevation/suspicious DRE finding (absolute)
– Severe lower urinary tract symptoms (LUTS) associated with BPH
– Erythrocytosis (hematocrit >52–54%)
– Uncontrolled/poorly controlled heart failure
– Untreated OSA, although no scientific evidence exists demonstrating a direct causal relationship between T and OSA
– Men seeking fertility
• Improvement is expected in:
– Reduction of body fat/visceral obesity (2)[A]
– Increase in fat-free mass/possibly muscle strength (1)[A]
– Insulin resistance/glycemic control in men with DMII (2)[A]
– Bone mineral density at lumbar spine (1)[A]
– Hypoactive sexual desire/ED/delayed ejaculation (1)[B]
• Considerations in the older male: The American Geriatrics Society (AGS) lists T as a medication to generally avoid in older adults because of potential for cardiac problems and men with personal history of prostate cancer.
• TRT agents/options outlined below
– Transdermal agents may have best compliance; all provide uniform T level for 24 hr
– Topical agents: Interpersonal transfer possible and should be avoided, especially for women and children
– Gels should be dry before putting on clothes over application site; delay swimming
– Brand names provided to avoid patient confusion; see FDA label for details
MEDICATION
First Line
• Buccal (Striant) 30 mg T/tab system
– Dose: 30 mg BID
– Avoids 1st-pass effect of hepatic inactivation
– Apply to gum over incisor; do not chew/swallow
• Transdermal (Androderm): Apply to nonscrotal skin (back, abdomen, upper arms, thighs); avoid bony prominences; delivery 2 mg or 4 mg T/patch
– Dose: Based on patch; start one 4 mg/patch/24 h; adjust to 1 or more patch combinations for desired effect
– Skin irritation may be noted; remove for MRI
• Transdermal gels; product-specific dosing; apply clean dry: Shoulder, upper arm, or abdomen
– (AndroGel 1%)
Dose: Topical daily 5–10 g (max)
– (AndroGel 1.62%)
Dose: Topical 2 pump activations or 40.5-mg pack; adjust from 1 activation 20.25 mg or single 20.25 mg pack; 81 mg/d (max)
– [Fortesta] 10 mg T/0.5 mg gel/activation; apply to inner thigh area only
Dose: Start 4 pump activations (40 mg) QAM; adjust 1–7 pump activations (10 mg–70 mg daily; 70 mg max
– (Testim 1%) 50 mg T/5 g gel; 50 mg/unit dose tube; apply shoulder or upper arm
Dose: Topical 5–10 g/d/2 tubes MAX
• Transdermal solution
– (Axiron) 30 mg T/1.5 mL of solution
Dose 60 mg T (1 pump = 30 mg of T solution to each axilla) daily; adjust based on levels
• IM short-acting formulations; may be associated with fluctuations in serum T (supraphysiologic 2–5 d after injection, subphysiologic 10–14 d after injection) which may be associated with symptom fluctuation
– T cypionate (Depo-Testosterone) 200–400 mg IM every 3–4 wk or 100–150 mg
– every 2 wk preferred
– T enanthate (Delatestryl) 100–400 mg IM every 4 wk or 100–150 mg every 2 wk preferred
– Prepubertal boys: 50–100 mg IM agent monthly or 25–50 mg every 2 wk, increase to 50–100 mg every 2 wk and then adult dose over 2–4 yr or until pubertal development occurs
• T implant
– Pellets (Testopel) (75 mg/each) 150–450 mg SC implant every 3–6 mo
– 2 pellets for each 25 mg T required weekly; in upper buttock with local anesthesia
– Local symptoms such as pain, bleeding
– Pellet infection and extrusion (up to 10%)
• Parenteral T undecanoate (Aveed): 750 mg IM (3 mL) initially, at 4 wk, then 750 mg every 10 wk
• T nasal gel (Natesto) 2 pumps each nostril (11 mg testosterone) one in each nostril TID (total 33 mg/day)
• T formulations outside the US:
– Oral T undecanoate: 40–80 mg PO with meals BID to TID
– T-in-adhesive matrix patch: 2 patches (4.8 mg T/d) applied every 2 days
– T gel 2%: 3–4 g (60–80 mg of T) applied to abdomen or both inner thighs daily
Second Line
Any agent form the Frist Line medication can be used as second line if the product is ineffective or there are proactical use issues with an individual patient
SURGERY/OTHER PROCEDURES
Insertion of subdermal T pellets (see above MEDICATION: First Line)
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
• There may be therapeutic synergism with combined TRT and phosphodiesterase-5 inhibitors in men with low T and ED (2)[A]
• Other forms of androgen therapy include the usage of dehydroepiandrosterone (DHEA), dihydrotesto-sterone (DHT), although their use has not been proven effective (2)[B]
• Human chorionic gonadotropin (hCG) may preserve spermatogenesis in young men with hypogonadism (1)[B] (See Section I “Testosterone, Decreased [Hypogonadism]”)
• Antiestrogens and aromatase inhibitors may raise endogenous T in secondary hypogonadism if the hypothalamic–pituitary–testicular axis is intact
• Selective androgen receptor modulators (SARMs) may have a role in hypogonadism
Complementary & Alternative Therapies
There are no alternative therapies that will cure low T. Some stress management techniques can relieve the stress and anxiety associated with hypogonadism: Yoga, meditation techniques, emotional support/counseling, healthy lifestyle (nutritious diet, active exercise, adequate rest)
ONGOING CARE
PROGNOSIS
• Goal is for the restoration of serum T within normal lab limits; supraphysiologic levels should be avoided (2)[C]
• Target serum T should be 40–70% of upper limit of normal serum T (2)[C]
• There is no evidence of benefit for maintaining a circadian rhythm of serum T (2)[C]
COMPLICATIONS
• Erythrocytosis; gynecomastia; fluid retention
• No conclusive evidence that TRT increases the risk of or worsens pre-existing prostate cancer or LUTS secondary to BPH. Men effectively treated for prostate cancer, after sufficient period of surveillance has elapsed (at least 1 yr), may be candidates for symptomatic TRT (1)[B]
– TRT should be reserved for patients with low-risk prostate cancer (Gleason grade <8, pT1-2, PSA <10 ng/mL)
– Men considering TRT in this context must be counseled and understand the theoretical risks and the fact that T medications carry prostate cancer risk labeling
FOLLOW-UP
Patient Monitoring
• Clinical and biochemical verification of treatment effect should occur 1–6 mo after initiating TRT (depending on TRT modality) (1)[C]
– Repeat assessment of serum T parameters
– Dosage may be adjusted if still subphysiologic
– Once the proper dose established, annual T measurements are usually sufficient
• Monitor hematocrit 3, 6, and 12 mo after initiating TRT, then annually (1)[A]
• Monitor prostate heath (DRE/PSA) 3, 6, and 12 mo after initiating TRT, then annually (1)[A]
• In men with known osteopenia or osteoporosis, bone mineral density should be verified after 6, 12, or 24 mo of TRT (1)[C]
• Monitoring lipids and glycemia is not routinely required for safety but should be done as part of general health maintenance
Patient Resources
Urology Care Foundation AUA. www.urologyhealth.org/urology/index.cfm?article=132
REFERENCES
1. Dohle GR, Arver S, Bettocchi C, et al. Guidelines on male hypogonadism. Uroweb. 2012. Available at: http://www.uroweb.org/gls/pdf/16_Male_Hypogonadism_LR%20II.pdf (Accessed May 13, 2014)
2. 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;10:245–284.
ADDITIONAL READING
Hsiao W, et al. The role of testosterone replacement therapy in contemporary urological practice. AUA Update. 2008;27 Lesson 40.
See Also (Topic, Algorithm, Media)
• Andropause (Late-Onset Male Hypogonadism)
• Erectile Dysfunction/Impotence, General Considerations
• Hyperprolactinemia
• Hypogonadism, Society Definitions
• Infertility
• See Specific Syndromes: Kallmann, Klinefelter, Laurence–Moon, Prader–Willi, Sertoli only
• Testosterone (Free and Total) Lab Testing
• Testosterone Replacement Following Localized Prostate Cancer Therapy
• Testosterone Replacement Therapy, Prostate Cancer Risk
• Testosterone, decreased (hypogonadism)
• Testosterone, decreased (hypogonadism) Algorithm 
CODES
ICD9
• 257.2 Other testicular hypofunction
• V07.4 Hormone replacement therapy (postmenopausal)
ICD10
• E29.1 Testicular hypofunction
• Z79.890 Hormone replacement therapy (postmenopausal)
CLINICAL/SURGICAL PEARLS
• Treatment is usually indicated for men with both symptoms and lab evidence of low serum T.
• The risks and benefits of each TRT modality should be thoroughly discussed.
• Post-TRT initiation, patient monitoring for treatment effect, biochemical resolution, and development of adverse effects is critical.
• Patients who have completed prostate cancer treatment for localized disease cancer treatment may cautiously be initiated on TRT in certain circumstances.