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A. Causes [1] navigator

  1. Gonadal Defects
    1. Genetic Defect - Klinefelter Syndrome, myotonic dystrophy, Prader-Willi Syndrome
    2. Polyglandular autoimmune failure syndromes (eg. Schmidt Syndrome)
    3. Anatomic Defects
    4. Toxins - cytotoxic agents, spironolactone
    5. Radiation
    6. Alcohol
    7. Orchitis - usually due to mumps
    8. Hypogonoadotropic Hypogonadism
  2. Hormone Resistance
    1. Androgen insensitivity
    2. Luteinizing hormone insensitivity
  3. Hypopituitarism [6]
    1. Idiopathic
    2. Tumor
    3. Other causes
  4. Hyperprolactinemia [7]
    1. Pituitary adenoma
    2. Dopamine antagonists - especially antipsychotics
    3. Fewer cases due to idiopathic increased prolactin production
    4. Many other causes including non-pituitary brain lesions
  5. Gonadotropin Deficiency [2]
    1. Hypogonadotropic Hypogonadism (see below)
    2. Hypothalamic Insufficiency
    3. LH or FSH Deficiency - very rare
    4. LH mutations (ß-subunit) - very rare [15]
  6. Systemic Diseases
    1. Chronic Diseases
    2. Anorexia / Malnutrition / Starvation
    3. High levels of exercise / physical exertion
    4. These systemic diseases suppress hypothalamic GnRH release
    5. This is called hypothalamic amenorrhea
    6. Massive obesity may also cause amenorrhea (possible estrogen overproduction)

B. Hypogonadotropic Hypogonadism [3,4] navigator

  1. Most cases are familial
  2. Mutations associated with hypogonadotropic hypogonadism (Table, Ref [4]) [12]
    1. KAL1 - GnRH deficiency with anosmia - Kallman Syndrome
    2. GPR54 - G-protein coupled receptor 54 [10]
    3. SF1 - steroidogenic factor 1
    4. DAX1 - DSS-AHC critical region on X chromosome
    5. DSS is dosage sensitive sex reversal gene, AHC is adrenal hypoplasia congenita
    6. GnRH Receptor - mutations in gonadotropin releasing hormone receptor
    7. FGFR1 - fibroblast growth factor receptor 1
    8. LEP - leptin; major pathway for obesity
    9. LEPR - leptin receptor
    10. Isolated congenital idiopathic GnRH deficiency
  3. Acquired GnRH deficiency is very uncommon
  4. Uncommon cause of male infertility
  5. Most patients respond to pulsatile GnRH administration
  6. Mutation in ß-subunit of FSH reported for in one male patient with hypogonadism [11]

C. Evaluationnavigator

  1. Serum testosterone or estrogen concentrations
  2. Serum FSH and LH
  3. Serum Prolactin
  4. Primary Hypogonadism
    1. Low testosterone or estrogen, high LH and/or FSH levels
    2. Fertility generally cannot be induced by hormone replacement
  5. Secondary Hypogonadism
    1. Low testosterone or estrogen, low FSH and/or LH
    2. Potentially fertile with hormone replacement

D. Treatmentnavigator

  1. Depends on cause
  2. Estrogen Replacement Therapy
    1. Cyclic estrogen + progesterone to induce menses
    2. Estrogen only replacement in post-menopausal women with histerectomy
    3. Chronic estrogen/progestin replacement in post-menopausal women with intact uterus
  3. Androgen Replacement Therapy
    1. Testosterone - various esters and formulations
    2. Moderate doses of testosterone replacement had no effect on prostate tissue in older men with late onset hypogonadism [14]
  4. Sustained Reversals
    1. Noted for normosmic or anosmic (Kallmann syndrome) forms in ~10% of patients following withdrawal of hormal therapy
    2. Therefore, brief withdrawal of hormone therapy and following endocrine levels should be considered in these patients

E. Androgen Replacement Therapies [8,9]navigator

  1. Testosterone Esters (intramuscular, im)
    1. Testosterone enanthate - 150-200mg IM q10-14 days
    2. Testosterone cypionate - 150-200mg IM q10-14 days
    3. Testosterone propionate - 20-50mg im three times per week
  2. Testosterone Patches (skin patch)
    1. Testoderm® - must be applied to (shaved) scrotal skin qd (4 or 6mg patch)
    2. Androderm® - apply to any skin surface, 2.5mg patch bid or 5.0mg patch qd
  3. Testosterone Gels (apply to skin)
    1. AndroGel® (5gm 1% gel) applied qd to skin, up to 10gm qd maximum
    2. Testim® (5gm 1% gel) applied qd to skin, up to 10gm qd maximum
  4. Fluoxymesterone - 10-20mg po qd
  5. Methyltestosterone - 10-40mg po qd
  6. Other Uses [2]
    1. Improve libido, muscle mass, hematocrit, energy in older men with low testosterone
    2. May improve weight gain, libido in patients with HIV infection and wasting
    3. Daily 90µL trasdermal testosterone improved sexual satisfuaction in premenopausal women with reduced libido and low serum-free testosterone levels [16]

F. Androgen Side Effects [13]navigator

  1. Depend on type of drug and dose administered
  2. Acne
  3. Hirsutism
  4. Fluid retention and weight gain
  5. Decreased testicular size and azoospermia
  6. Increased or decreased libido
  7. Increased aggression and/or psychotic symptoms
  8. Erythrocytosis - increased red cell mass; frank polycythemia may occur
  9. Reduction in HDL levels
    1. May increase LDL levels
    2. Reduces Lp(a) levels
  10. Liver Dysfunction
    1. Hemorrhagic liver cysts (peliosis hepatis)
    2. Cholestasis with possible jaundice or liver failure
    3. Hepatocellular carcinoma may occur
  11. Sleep Apnea
  12. Effects on Prostate
    1. Concern for prostate hyperplasia, either benign or increased risk of malignant progression
    2. Testosterone enanthate 150mg IM q2 weeks x 6 months had no effect on prostate tissue in older men with late onset hypogonadism [14]
    3. Concentrations of testosterone in prostate tissue with this regimen were low, despite achieving normal serum levels of testosterone [14]

G. Treatment of Hyperprolactinemia [5] navigator

  1. Hyperprolactinemia due to Pituitary Tumors
    1. Majority of cases are due to prolactin (PRL) secreting pituitary tumors
    2. Minority of cases due to hyperfunctioning prolactin-secreting pituitary cells
    3. Also need to rule out pituitary "stalk compression" syndrome
    4. This occurs due to macroadenoma or cosecretion of growth hormone + PRL
  2. Dopamine inhibits PRL secretion and can be used to reduce PRL levels
  3. Bromocriptine (Parlodel®)
    1. D1 and D2 dopamine agonist
    2. Dose is 2.5mg po bid restores menses in >50% of women
  4. Cabergoline (Dostinex®)
    1. D2 dopamine selective agonist
    2. Cabergoline is apparently more effective and better tolerated than bromocriptine
    3. Usual starting dose of cabergoline is 0.25mg twice weekly, increase to 0.5mg if needed
    4. Cabergoline also showed shrinkage of macroadenomas

References navigator

  1. Bagatell CJ and Bremner WJ. 1996. NEJM. 334(9):707
  2. Adashi EY and Hennebold JD. 1999. NEJM. 340(9):709 abstract
  3. Nachtigall LB, Boepple PA, Pralong FP, Crowley WF Jr. 1997. NEJM. 336(6):410 abstract
  4. Beier DR and Dluhy RG. 2003. NEJM. 349(17):1589 abstract
  5. Cabergoline. 1997. Med Let. 39(1003):58 abstract
  6. Lamberts SWJ, de Herder WW, van der Lely AJ. 1998. Lancet. 352(9122):127
  7. Colao A and Lombardi G. 1998. Lancet. 352(9138):1455 abstract
  8. Testosterone. 1997. Med Let. 38(975):49
  9. Testosterone Products. 2003. Med Let. 45(1164):70 abstract
  10. Seminara SB, Messager S, Chatzidaki EE, et al. 2003. NEJM. 349(17):1614 abstract
  11. Phillip M, Arbelle JE, Segev Y, Parvari R. 1998. NEJM. 338(24):1729 abstract
  12. MacLaughlin DT and Donahoe PK. 2004. NEJM. 350(4):367 abstract
  13. Rhoden EL and Morgentaler A. 2004. NEJM. 350(5):482 abstract
  14. Marks LS, Mazer NA, Mostaghel E, et al. 2006. JAMA. 296(19):2351 abstract
  15. Lofrano-Porto A, Barra GB, Giacomini LA, et al. 2007. 357(9):897 abstract
  16. Davis S, Papalia MA, Norman RJ, et al. 2008. Ann Intern Med. 148(8):569 abstract