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androgen_defic

androgen deficiency

see androgens

introduction

  • clinical picture depends on when the androgen deficiency begins:
    • pre-pubertal ⇒ eunuchoidism
      • tall (as epiphyses remain open), narrow shoulders, small muscles, adult female body habitus, small genitalia, high-pitched voice, sparse pubic & axillary hair with female pattern
    • adult life ⇒ slow regression of sex characteristics as requires only little androgen to maintain them

aetiology:

the male "menopause":

androgens with aging:

  • total testosterone levels start declining in the fifth decade of life due to:
    • primary gonadal failure:
      • decrease in the number and volume of the Leydig cells
      • impaired steroid hormone biosynthesis
      • impaired blood supply to the gonads
      • decreased steroid output after administration of human chorionic gonadotropin
    • altered hypothalamic-pituitary axis:
      • there is loss of diurnal variation in secretion of gonadotropin & thus testosterone
      • blunted luteinizing-hormone response to gonadotropin-releasing-hormone stimulation
      • decreased or absent response of luteinizing-hormone levels to naloxone or tamoxifen
      • increased gonadotrophic sensitivity to testosterone feedback
    • serum sex-hormone-binding globulin concentration increases:
      • ? due to increased oestradiol production from increased adiposity
    • although andropausal men remain fertile, there is a decrease in spermatogenesis and sperm motility with age due to:
      • a decrease in the number and function of Sertoli cells with aging, resulting in an increase in follicle-stimulating-hormone levels and a decrease in inhibin levels

iatrogenic androgen deficiency:

other conditions:

  • Klinefelter's syndrome
  • myotonic dystrophy:
    • X-linked inherited disease (DM1 or DM2 gene locus) characterised by:
      • progressive muscle weakness
      • hyperexcitability of muscle membrane (myotonia) - unable to let go with hand-shake
      • testicular atrophy with frontal baldness
      • insulin resistance, ocular cataracts, polyhydramnios & sustained re-entrant VT
  • congenital 5-alpha reductase deficiency:
    • common in certain parts of Dominican Republic
    • male pseudohermaphroditism:
      • male internal genitalia including testes
      • female external genitalia & thus raised as girls, but when they reach puberty, circulating testosterone increases & they develop male body, male libido, clitorimegaly (“penis-at-12” syndrome) to the point that some can have intercourse with women. They thus tend to change gender identities & become boys although they tend to have little facial hair or baldness
      • lack prostate development in fetal and adult life
  • congenital adrenal hyperplasia:
    • cholesterol desmolase deficiency results in compromised conversion of cholesterol to pregnenolone, resulting in low cortisone and sex hormone levels, causing diffuse adrenal insufficiency and feminisation with resultant high ACTH levels causing adrenal hyperplasia. Most die soon after birth.
  • 17-alpha hydroxylase deficiency (rare):
    • no sex hormones produced ⇒ female external genitalia regardless of sex

effects of low androgen levels in the adult male:

  • osteoporosis
    • ? role of leptins acting on hypothalamus to inhibit bone mineralisation centrally as well as promoting fertility
    • does obesity help prevent osteoporosis by causing leptin resistance?
  • sexual dysfunction:
    • testosterone is necessary for libido, erectile function, and normal ejaculation
    • oestrogens may have a role in determining sexual function in men (oestrogen is mainly from metabolism of testosterone)
    • bio-available testosterone levels correlate strongly with nocturnal penile tumescence, especially in men 55 to 64 years of age
    • in hypogonadal men, testosterone Rx increases penile rigidity and in the number of erectile events per hour.
  • ? association with prostate cancer
  • loss of anabolic actions:
    • decrease in muscle strength and mass:
      • men lose muscle strength with aging
      • from the fourth decade onward, there is a decrease of 8% to 10% in peak torque per decade
      • muscle protein synthesis decreases by 55%, and there is a decrease in myosin heavy chain fibers with an increase in the deposition of connective tissue and fat in muscle. The decrease in muscle parallels the decrease in testosterone concentration
      • men with primary hypogonadism have been shown to develop weakness of limb-girdle muscles
      • in young hypogonadal men, replacement doses of testosterone increase muscle mass and strength
    • increase in body fat
      • abdominal obesity in men is often associated with low serum testosterone concentrations, testosterone administration decreases abdominal fat and increases lean body mass
    • loss of vascular tone?
    • high levels of plasminogen activator inhibitor-1, thus inhibiting the fibrinolytic process
    • decrease in hemoglobin and hematocrit values:
  • depression & cognitive dysfunction:
    • bio-available testosterone levels are inversely associated with depression, higher levels of testosterone are also associated with better mental control and long-term verbal memory
    • in hypogonadal men, testosterone replacement improves mood and sense of well-being, reduces anxiety, and improves concentrating ability
    • testosterone replacement enhances spatial cognition in elderly men
    • testosterone reduces neuronal secretion of beta-amyloid peptide, the major protein in plaques of patients with Alzheimer's disease
  • auto-immune disease

clinical assessment of suspected androgen deficiency:

  • as many of the features in the elderly are non-specific (eg. fatigue, weakness, depression), history & examination should look for evidence of androgen deficiency and its possible causes:
    • history:
      • frequency of shaving, loss of body hair, libido and sexual performance
      • history of osteoporosis, fractures, and mood changes
      • headaches, visual complaints, head trauma, testicular trauma or infection, and medications
    • examination:
      • inspection of body hair, breast size, visual fields, and genitals
    • investigation:
      • early morning serum total testosterone level:
        • if it is less than 300 ng/dL, the patient should be considered hypogonadal & thus need to exclude treatable causes:
          • serum prolactin:
            • elevated prolactin level may indicate the presence of a pituitary tumor
          • thyroid-stimulating hormone:
            • if hypothyroid, start Rx with thyroxine as per usual
          • gonadotropin levels:
            • low gonadotropin levels indicate central hypogonadism

Rx of male androgen deficiency:

testosterone replacement Rx:

benefits:

  • improved bone density, muscle strength, improved haemtocrit, reduced adiposity
  • improved sexual function
  • improved cognition, decreased depression

risks:

  • obstructive sleep apnoea in susceptible pts which may be lethal if subclinical IHD by causing nocturnal desaturation resulting in arrhythmias

C/I:

  • prostate Ca

options:

  • parenteral testosterone esters:
    • cheap, requires injections every 2 weeks, may be painful
    • rapid peaks & gradual decrease which may effect mood, no circadian variation
  • trans-scrotal testosterone patch:
    • requires dry shaving of scrotum; may fall off; worn for 22-24hrs;
    • expensive, increased scrotal DHT levels, mimics circadian secretion; good clinical response;
  • trans-dermal testosterone patch:
    • usually requires 2 patches; does not need scrotal shaving; worn for 24hrs per day; minority may not achieve adequate levels; expensive;
  • DHEA replacement Rx:
    • dehydroepiandrosterone (DHEA) is a weak androgen and is a precursor of both estrogens and androgens
    • 50mg/d may increase bone density, increase muscle strength & decrease adiposity
  • selective androgen receptor modulators:
    • in research only at present

references:

  • Hypogonadism and Androgen Replacement Therapy in Elderly Men. AmJMed May 2001 Volume 110(7):  pp 563-572
androgen_defic.txt · Last modified: 2019/06/17 23:29 (external edit)