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Male Hypogonadism. Michael Jakoby, MD/MA Clinical Associate Professor of Medicine Chief, Division of Endocrinology. Case.

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male hypogonadism

Male Hypogonadism

Michael Jakoby, MD/MA

Clinical Associate Professor of Medicine

Chief, Division of Endocrinology

slide2
Case

A 26 yo white male is referred due to sexual dysfunction. Since marriage 6 months ago, the patient has not always been able to achieve an erection sufficient for intercourse. He was sexually abstinent before marriage. Libido is “fair to poor.” Growth of pubic hair and shaving occurred between 15 and 17 years. Exercise tolerance was “good.” Testes have always been “small.” There was no head trauma, loss of smell, testicular trauma, testicular surgery, or treatment for cancer. The patient denied chronic illness or taking medication. Family history was unremarkable.

Exam: 71 in (180 cm) 76 kg, armspan 181 cm

crown to pubis 89 cm, pubis to floor 91 cm

typical male muscle mass, body and pubic hair somewhat sparse, normal appearing phallus

both testes descended, firm, NT, no masses, 3-4 cc

definition
Definition

Decrease in one or both of the two major functions of the testes.

clinical features
Clinical Features

*Arm span > 2 cm longer than vertical height; lower body segment > 2 cm longer than upper body segment

screening for androgen deficiency
Screening for Androgen Deficiency

The Endocrine Society recommends against screening for androgen deficiency in the general population

  • Infertility
  • Sellar mass, radiation, or surgery
  • Osteoporosis or low trauma fracture
  • HIV-associated weight loss
  • ESRD
  • COPD (moderate to severe)
  • Type 2 diabetes mellitus
  • Medications that effect testosterone production
    • Glucocorticoids
    • Opiates
    • Ketoconazle
history
History
  • Symptoms onset
  • Testicular size
  • Breast enlargement
  • Behavioral abnormalities
  • Chemotherapy or radiation therapy
  • Alcoholism
  • Visual field defects
  • Medications
examination
Examination
  • Testicular size
  • Pubic hair
  • Gynecomastia
  • Muscle mass
  • Body proportions
  • Fundoscopy & visual fields screening
testosterone measurements
Testosterone Measurements
  • Total testosterone (free + protein bound) is almost always an accurate measure of testosterone secretion
  • Free testosterone should be measured by equilibrium dialysis; analog methods commonly available give results proportionate to SHBG levels (Vermeulin A JCEM 84:3666)
  • Testosterone should be measured in the morning (~ 8 AM) due to diurnal variations in testosterone levels, especially in young men
  • Conditions that predispose to low SHBG levels:
    • Obesity (BMI > 40)
    • Senescence
    • Nephrotic syndrome
    • Cirrhosis
    • Anticonvulsants
testosterone in obese men
Testosterone in Obese Men

Comparisons of total and free testosterone between morbidly obese men (BMI > 40) and age-matched controls.

Glass AR et al. JCEM (1977) 45:1211

standard semen analysis
Standard Semen Analysis
  • Typically ordered for infertility w/u only
  • Normal specimen:
    • > 40 million sperm/ejaculate
    • > 50% motile; > 25% rapidly motile
    • > 50% normal morphology
ddx primary hypogonadism
Klinefelter’s syndrome

Gonadotropin receptor mutations

Cryptorchidism

Androgen biosynthesis disorders

Varicocele

Congenital anorchia

Mumps orchitis

Radiation

Antineoplastic drugs

Ketoconazole

Glucocorticoid excess

Trauma

Testicular torsion

Autoimmune orchitis

Cirrhosis

Chronic renal failure

HIV infection

Idiopathic

DDx: Primary Hypogonadism

Congenital

Acquired

ddx secondary hypogonadism
Isolated hypogonadotropic hypogonadism

Kallman’s syndrome

DAX1 mutation

GPR 54 mutation

Leptin or leptin receptor mutations

Gonadotrope receptor mutations

Hypopituitarism

Hyperprolactinemia

Androgen therapy

GnRH analog therapy

Glucocorticoid therapy

Critical illness

Chronic illness

Diabetes mellitus

Opiates

Pituitary mass lesions

Infiltrative diseases

Sellar surgery

Sellar radiation

DDx: Secondary Hypogonadism

Congenital

Acquired

slide18
Case

How would you evaluate this patient?

Total testosterone: 134 ng/dL (176-781)

Luteinizing hormone (LH): 26.3 mIU/mL (1.3-13.0)

What is the initial diagnosis?

Primary hypogonadism

What is the next step in work up?

ddx primary hypogonadism19
Klinefelter’s syndrome

Gonadotropin receptor mutations

Cryptorchidism

Androgen biosynthesis disorders

Varicocele

Congenital anorchia

Mumps orchitis

Radiation

Antineoplastic drugs

Ketoconazole

Glucocorticoid excess

Trauma

Testicular torsion

Autoimmune orchitis

Cirrhosis

Chronic renal failure

HIV infection

Idiopathic

DDx: Primary Hypogonadism

Congenital

Acquired

evaluation of men with androgen deficiency
Evaluation of Men with Androgen Deficiency

Confirmed low testosterone

Check LH+FSH (SA if infertility)

High gonadotropins – 1o

Low/low nl gonadotropins – 2o

Prolactin, other pituitary hormones, iron studies, sella MRI

Karyotype

slide21
Case

How would you evaluate this patient?

Total testosterone: 134 ng/dL (176-781)

Luteinizing hormone (LH): 26.3 mIU/mL (1.3-13.0)

What is the initial diagnosis?

Primary hypogonadism

What is the next step in work up?

Karyotype: 47 XXY

klinefelter s syndrome
Klinefelter’s Syndrome
  • Incidence ~ 1/1,000 live male births
  • Extra X chromosome, usually 47 XXY
  • Phenotype strongly influenced by CAGn repeat in the androgen receptor gene
  • Manifestations
    • Hypogonadism
    • Gynecomastia
    • Behavioral disorders
    • Bronchiectasis/emphysema/bronchitis
    • Mediastinal germ cell tumors
    • Non-Hodgkin’s lymphoma
    • Diabetes mellitus
    • Lower extremity varicosities
gonadal manifestations of klinefelter s syndrome
Gonadal Manifestations of Klinefelter’s Syndrome

Gordon DL et al. Arch Intern Med (1972) 130:720

testosterone replacement
Testosterone Replacement
  • Primary goal is to restore testosterone levels to the laboratory reference range
  • Prescribe only for patients with confirmed hypogonadism
  • Role in “treating” decline in testosterone levels with aging uncertain
  • Multiple preparations
    • Oral
    • Intramuscular
    • Transdermal
    • Buccal
oral testosterone preparations
Oral Testosterone Preparations
  • Alkylated testosterone more slowly metabolized by liver than native testosterone
  • May not induce virilization in adolescents
  • Untoward effects
      • Cholestatic jaundice
      • Peliosis hepatis
      • Hepatocellular carcinoma
intramuscular testosterone
Intramuscular Testosterone
  • Enanthate and cypionate esters of testosterone
  • Lipophilic, leading to sustained release from muscle depots
  • Side effects related to dosing or administration
  • Regimens of 100 mg q wk to 300 mg q 3 wks acceptable
  • Goal is a mid-cycle level near the middle of the laboratory reference range
intramuscular testosterone27
Intramuscular Testosterone

Serum testosterone levels after a single 200 mg IM dose of testosterone enanthate.

Snyder PJ et al. JCEM (1999) 51:1335

transdermal testosterone
Transdermal Testosterone
  • Patch (Androderm)
    • Apply to skin of upper arms and torso
    • Delivers 5 mg testosterone/24 hr in continuous manner
    • Approximately 1/3 of patients develop significant contact dermatitis
  • Gels (Androgel, Testim)
    • Apply to skin of upper arms and torso
    • Usually dosed as 5.0 g or 10.0 g of gel to deliver 50 mg or 100 mg testosterone, respectively in a continuous manner
    • Reports of contact dermatitis and gel odor uncommon
transdermal testosterone29
Transdermal Testosterone

Serum testosterone levels after single applications of a 5 mg Androderm patch and 5.0 g and 10.0 g testosterone gel doses.

Snyder PJ et al. JCEM (1999) 51:1335

desirable effects of testosterone therapy
Desirable Effects of Testosterone Therapy
  • Virilization (incompletely virilized men)
  • Increased libido and energy
  • Improved erectile function?
  • Increased muscle mass and strength (8-10 wks)
  • Increased bone mass (full effect ~ 24 mo)
untoward effects of testosterone therapy
Untoward Effects of Testosterone Therapy
  • Pain at injection site (IM preparations)
  • Contact dermatitis (patch >> gel)
  • Acne or oily skin
  • Gynecomastia
  • Aggressive behavior (adolescents)
  • Short stature (adolescents)
  • Increased prostate volume/PSA
  • Urinary retention (BPH exacerbation)
  • Sleep apnea
  • Erythrocytosis
contraindications to testosterone therapy
Contraindications to Testosterone Therapy
  • Very high risk of adverse outcomes
    • Prostate cancer
    • Breast cancer
  • High risk of adverse outcomes
    • Undiagnosed prostate nodule
    • Unexplained PSA elevation
    • BPH with severe urinary retention
    • Erythrocytosis
    • NYHA Class III or IV heart failure
pre treatment screening
Pre-treatment Screening
  • Digital rectal exam
  • History of urinary retention (urodynamic studies, bladder US PRN)
  • History of sleep apnea symptoms (polysomnography PRN)
  • PSA (urology referral if > 4 ng/mL)
  • CBC
treatment monitoring
Treatment Monitoring
  • Serum testosterone
    • IM testosterone: midpoint between injections, level near middle of reference range
    • Patch: 3-12 hrs after applying new patch
    • Gel: timing not critical
    • Buccal pellet: immediately before or after new pellet
  • Prostate
    • DRE @ 3 months, then annually
    • PSA @ 3 months, then annually
    • Prostate biopsy if PSA > 4 ng/mL, PSA increases by > 1.4 ng/mL in 12 months, or PSA velocity > 0.4 ng/mL/yr
  • Red cell mass
    • CBC at 3 months, then annually
    • If Hct > 54%, stop therapy, monitor for return to reference range, then resume therapy at a lower dose
slide35
Case

How would you manage this patient?

Androgel 5 g topically QD

Counseling regarding infertility and extragonadal manifestations of Klinefelter’s syndrome

Make patient aware of Klinefelter’s support groups

summary
Summary
  • Signs and symptoms of hypogonadism depend on when the condition occurs in development
  • Initial evaluation focuses on distinguishing between primary and secondary hypogonadism
    • Primary: LH elevated, testosterone low
    • Secondary: LH low, testosterone low
  • Goal of testosterone replacement is physiological testosterone levels and preservation of testosterone-dependent physiological functions