Philip T. Zhao, MD
Allen D. Seftel, MD
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
– Usually associated with impaired sperm production; or with an isolated impairment of sperm production or function with normal T production.
• T is essential for:
– Normal sexual function, growth and development of male sexual organs, and maintenance of male secondary sexual characteristics
• Normal levels and function result in:
– Enhanced libido, increased energy, and production of RBCs; osteoporosis protection
• In utero hypogonadism
– Ambiguous genitalia, normal female genitalia, microphallus, pseudovaginal perineoscrotal hypospadias, bifid scrotum, cryptorchidism
• Prepubertal hypogonadism:
– Delayed puberty, microphallus, small testes, no male hair pattern, disproportionately long arms/legs, high-pitched voice, poor muscle mass
• Postpubertal/adult hypogonadism:
– Lack of libido, erectile dysfunction (ED), hot flushes/sweats, gynecomastia, spermarche, infertility (oligospermia/azoospermia), poor vitality, depression, increased body fat/BMI, osteopenia/osteoporosis, hypercholesterolemia
EPIDEMIOLOGY
Incidence
N/A
Prevalence (1)
• 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
• Testicular trauma/orchiectomy
• Medications
– Decreased T production: Dopamine antagonists, corticosteroids, ethanol, ketoconazole, GnRH analogues/antagonists, metoclopramide
– Decreased conversion of T to dihydrotestosterone (DHT): 5α-Reductase inhibitors
– Androgen receptor blockade: Flutamide, spironolactone, cyproterone, cimetidine
• Infections (mumps orchitis, HIV)
• Medical conditions:
– Iron toxicity to pituitary gonadotrophs, autoimmune diseases, endstage renal disease (ESRD)/uremia, histiocytosis X, pituitary apoplexy, myotonic dystrophy
Genetics
• Klinefelter syndrome
• Kallmann syndrome; mutation in Dax-1
• Laurence–Moon–Bardet–Biedl syndrome
• Prader–Willi syndrome
• Y chromosome microdeletion
• Congenital androgen resistance/insensitivity
• Alstrom, Rud, Bloom syndromes; mutations in leptin
PATHOPHYSIOLOGY
• T is regulated by the hypothalamic–pituitary–testicular axis
• Gonadotropin-releasing hormone (GnRH) neurons originate in the olfactory placode and migrate through the cribriform plate of the ethmoid to localize in the hypothalamus.
• Hypothalamus secretes GnRH, stimulates the pituitary to secrete leuteinizing hormone (LH) and follicle-stimulating hormone (FSH).
• GnRH pulse amplitude and frequency activate intracellular signalling mechanisms, which results in differential gene expression of the 2 subunits forming LH and FSH.
• LH stimulates testis Leydig cells to produce T. Feedback inhibition by T on the hypothalamus and pituitary maintains hormonal balance.
• FSH stimulates Sertoli cells to support spermatogenesis and secrete inhibin, which provides feedback on the pituitary
• Week long night/day shift work does not seem to change T levels
• T levels decrease 0.8–1.6% per year in men aged 40–70
ASSOCIATED CONDITIONS
• Increased risk for developing type 2 diabetes mellitus, metabolic syndrome, cardiac events, and a general reduction in survival
– Impact on cardiac events is controversial with most publications supporting a protective effect of “normal” T levels
GENERAL PREVENTION
Screening: The Endocrine Society in US recommends against screening for androgen deficiency in the general population.
DIAGNOSIS
HISTORY
• Development:
– Genital abnormalities (eg, hypospadias, microphallus, cryptorchidism); delayed sexual development/growth; need for hormone therapy; family history of delayed puberty or reproductive disorders; psychological impact of delayed puberty or growth; difficulty in school or learning disability; inability or reduced ability to smell
• Sexual function:
– Poor erections; reduced spontaneous, nighttime, morning erections; inability to perform sexually; decreased sexual activity; inability to father children despite unprotected sexual relations (>1 yr); small or shrinking testes
• Brain function:
– Poor general well-being; reduced sexual desire, interest, and motivation (libido); poor energy/vitality; excessive fatigue; poor motivation and initiative, passivity, low self-confidence/self-esteem; depressed mood; irritability; difficulty sleeping; hot flushes/sweats; poor concentration and memory
• Body function
– Decreased muscle bulk/strength; reduced physical activity or performance; breast enlargement/tenderness, especially if recent in onset; height loss, history of low trauma or vertebral compression fractures, osteopenia, or osteoporosis; body hair loss; reduced beard growth and shaving frequency.
PHYSICAL EXAM
• Assess height and eunuchoidal proportions:
– Arm span >2 cm > height; heel–pubis >2 cm > pubis–crown normal
• Secondary sexual characteristics, gynecomastia, bone age determination
• External genitalia: Testis and phallus
– Testis volume
Measure with a Prader orchidometer (normal adult 15–25 mL)
<6 mL characteristic of prepubertal hypogonadism
Soft and atrophic but normal sized suggestive of postpubertal hypogonadism
Small, firm suggests Klinefelter syndrome
– Genital ambiguity; hypospadias/micropenis
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• There is no consensus among specialists (endocrinologists, urologists, pathologists) as to what lab values define a “low” T level.
• The Food and Drug Administration (FDA) uses a cutoff value of 300 ng/dL to define hypogonadism for clinical trial development and enrollment.
• Society definitions of T levels and hypogonadism are summarized in Section II: “Hypogonadism, Society Definitions”.
• Total T concentrations are affected by alterations in sex hormone-binding globulin (SHBG), and T levels may be suppressed transiently with illness, certain medications, and some nutritional deficiencies
• If an isolated serum T is low, measure an early morning total serum T, bioavailable T (useful in equivocal cases), and LH.
• If the morning T is low, check serum prolactin:
– Prolactin elevated: Obtain MRI and consult with an endocrinologist
– Prolactin normal/low: 1) LH elevated: Primary hypogonadism; 2) LH normal/low: Obtain serum FSH and evaluate causes of secondary hypogonadism in consultation with an endocrinologist
Imaging
MRI if lab suggests pituitary tumor
Diagnostic Procedures/Surgery
N/A
Pathologic Findings
Atrophic testes in primary hypogonadism
DIFFERENTIAL DIAGNOSIS
• Hypergonadotropic hypogonadism (primary testicular failure); inadequate production of T despite adequate/elevated levels of LH/FSH:
– Klinefelter syndrome (most common); congenital XXY karyotype (1 in 576 male births)
– Impaired secretion of T and spermatogenesis
– Cryptorchidism, varicocele, bilateral anorchia
– Gonadal failure (chemotherapy/radiotherapy)
– Inactivating mutations of GnRH or gonadotropin receptor
• Hypogonadotropic hypogonadism (secondary hypogonadism): Inadequate stimulation of production of testicular androgen/spermatogenesis (low FSH/LH associated with low T)
– Kallmann syndrome: Abnormal migration of the GnRH neurons; anosmia and small testes
– Adrenal hypoplasia congenita: Constitutional delay of growth and puberty
– Chronic illness (celiac disease, Crohn disease, sickle cell, cystic fibrosis, diabetes)
– Malnutrition, hyperprolactinemia, hypothyroidism
– Hypopituitarism: Congenital vs. acquired (radiotherapy, CNS malignancy, infection, trauma)
– Isolated gonadotropin deficiency
– Congenital: Kallmann syndrome
– Acquired: Intracranial neoplasm (craniopharyngiomas, gliomas, prolactinomas)
– Syndromes with hypogonadotropism: See “Genetics” above
TREATMENT
GENERAL MEASURES
• Treatment should be guided by the intentions and desires of the patient.
• Avoid T replacement in a man with infertility seeking to regain fertility.
• Consider whether low serum T might be transient suppression caused by a critical, acute/subacute illness, or recovery from an acute illness; short-term use of certain medications; transient malnutrition; or excessive and chronic strenuous endurance exercise.
• A consensus statement from a group of professional societies (ISA, ISSAM, EAU, EAA, and ASA see Section II: “Hypogonadism, Society Definitions”) recommended (2,3):
– T >350 ng/dL do not treat
– T <230 ng/dL (with symptoms) may require T replacement therapy (TRT)
– Levels between 230–350 ng/dL, the recommendation is to repeat the T with SHBG for calculation of free testosterone or direct measurement of free testosterone by equilibrium dialysis.
– It has been previously recommended that men with T <200 ng/dL be treated as hypogonadal; T >400 ng/dL be considered normal and those with TT 200–400 ng/dL be treated based on their clinical presentation if symptomatic.
• Hypogonadotropic hypogonadism:
– Treat the underlying cause
– TRT may still be required
• Hyperprolactinemia:
– Discontinue offending medications
– Dopamine agonists (bromocriptine)
• If fertility is not desired, TRT may be instituted.
• Obtain baseline digital rectal exam (DRE), CBC, lipid profile, PSA
– T replacement may be associated with lipid abnormalities, polycythemia, azoospermia, sleep apnea, and possible prostatic changes.
• The overall goal of TRT is to correct or improve the clinical manifestations of androgen deficiency in men
• 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; delivers 2- 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 (10–70 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 days after injection, subphysiologic 10–14 days 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
– (Testopel) pellets (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%)
– T nasal gel (Natesto) 2 pumps each nostril (11 mg testosterone) one in each nostril TID (total 33 mg/day)
• T formulations outside US:
– Oral T undecanoate: 40–80 mg PO with meals BID to TID
– Parenteral T undecanoate: 1,000 mg IM initially, at 6 wk, then 1,000 mg every 10–14 wk; long lasting
– 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 of the agents noted as First line can be potentially used a second line alternative agents
SURGERY/OTHER PROCEDURES
Pituitary adenoma: Transsphenoidal resection
ADDITIONAL TREATMENT
Radiation Therapy
• Pituitary microadenoma or macroadenoma (>1.0 cm):
– Transsphenoidal resection ± radiation therapy
Additional Therapies
• If hypogonadotropic: May provide GnRH/gonadotropins to stimulate testicular production of androgen
• To initially stimulate T and sperm production:
– Human chorionic gonadotropin (hCG): 500–2,000 IU given SQ 2–3x weekly to maintain serum T levels within the normal range for 6–12 mo
• Added to hCG to stimulate sperm production:
– FSH/human menopausal gonadotropin (hMG), human FSH (hFSH), recombinant human FSH (rhFSH): After 6–12 mo of hCG treatment alone resulting in normal T levels, add FSH 75–300 IU is given SQ 3 times weekly for an additional 6–12 mo or longer
• To stimulate T/sperm production:
– GnRH: 5–25 ng/kg SQ every 2 hr by programmable infusion pump for 6–12 mo
Complementary & Alternative Therapies
• There are no alternative therapies that will cure hypogonadism
– No data to support the use of over the counter or direct to consumer “natural” T supplements.
• 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
Excellent ability to restore T levels to the normal range by adjusting dosage of medication and improve symptoms of hypogonadism (4)
COMPLICATIONS
• Hypogonadism (5):
– “Metabolic syndrome”: Anemia, increased fasting blood sugar, increased uric acid, increased cholesterol, increased body fat
– Appetite changes (increased or decreased)
– Balance problems
– Body hair loss
– Dry eyes
– Edema or leg pain
– Fatigue
– GI and/or respiratory disturbances
– Gynecomastia/breast tenderness
– Hot flushes/flashes/sweats
– Loss of libido/impotence
– Muscle weakness/wasting
– Osteoporosis
– Psychologic: Depression, memory difficulties, emotional lability
– Testicular atrophy
– Weight gain/increased body fat
• T replacement:
– Fluid retention
– Gynecomastia
– Hepatotoxicity
– Sleep apnea
– Theoretical risk of progression of prostate cancer: Unsubstantiated in recent studies
FOLLOW-UP
Patient Monitoring
• Every 3 mo (CBC, PSA, DRE) after starting treatment annually for response and adverse effects
• In men with known osteopenia or osteoporosis, bone mineral density should be verified after 6, 12, or 24 mo of TRT
• Monitoring lipids and glycemia is not routinely required for safety but should be done as part of general health maintenance
Patient Resources
• Guidelines on male hypogonadism (U.S. Department of Health & Human Services). http://guideline.gov/content.aspx?id=37626
• Urology Care Foundation AUA. www.urologyhealth.org/urology/index.cfm?article=132
REFERENCES
1. Morales A. Androgen deficiency in the aging male. In: Melmed S, Polonsky KS, Larsen PR, et al., eds. Williams Textbook of Endocrinology. 12th ed. Philadelphia, PA: Saunders; 2011:688–777.
2. 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 Metab. 2010;95:2536–2559.
3. Wang C, Nieschlag E, Swerdloff R, et al. Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations. Eur J Endocrinol. 2008;159:507–514.
4. Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in men. J Clin Endocrinol Metab. 2007;92:4241–4247.
5. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93:68–75.
ADDITIONAL READING
Paduch DA, Brannigan RE, Fuchs EF, et al. The Laboratory Diagnosis of Testosterone Deficiency: AUA White Paper. Available at http://www.auanet.org/common/pdf/education/clinical-guidance/testosterone-deficiency-whitepaper.pdf. Accessed March 27, 2014.
See Also (Topic, Algorithm, Media)
• Hyperprolactinemia
• Hypogonadism, Society Definitions
• Infertility
• Kallmann Syndrome
• Klinefelter Syndrome
• Laurence–Moon–Bardet–Biedl Syndrome
• Prader–Willi Syndrome
• Testosterone (Free and Total) Lab Testing
• Testosterone Replacement Therapy, General Principles
• Testosterone, Decreased (Hypogonadism) Algorithm 
CODES
ICD9
• 257.2 Other testicular hypofunction
• 792.2 Nonspecific abnormal findings in semen
• 799.81 Decreased libido
ICD10
• E29.1 Testicular hypofunction
• R68.82 Decreased libido
• R86.9 Unsp abnormal finding in specimens from male genital organs
CLINICAL/SURGICAL PEARLS
• Early morning serum total T below 300 ng/dL on at least 2 occasions in a symptomatic man usually confirms hypogonadism.
• Gonadotropins (LH and FSH) distinguish between a primary and a secondary cause.
• When caused by pituitary adenoma, patients can have additional symptoms due to mass effects, such as headaches or peripheral visual disturbance. There may also be signs and symptoms of other pituitary hormone deficiencies.
• Low T might be transient suppression (critical, acute/subacute illness, short-term use of certain medications; transient malnutrition; or excessive and chronic strenuous endurance exercise).