User Tools

Site Tools


androgens

androgens

introduction

  • androgens are substances that directly result in androgenic effects

androgenisation may occur via:

  • increased bioavailable androgen levels:
    • increased free testosterone:
      • increased total testosterone:
        • adrenogenital syndrome (v. uncommon):
          • 21beta hydroxylase (90% cases) or 11 beta hydroxylase (1% cases) deficiencies result in inability to synthesise cortisone & thus the resultant high ACTH levels cause build up of steroids which get shunted into manufacture of androgens resulting in virilisation & if severe in females, female pseudohermaphroditism although masculinisation may not appear marked until later in life, & mild cases only on biochemical testing. 
        • androgen-secreting Leydig cell testicular tumours (rare) ⇒ precocious pseudopuberty
        • puberty (males & females)
      • decreased sex hormone binding globulin:
    • increased conversion from testosterone via increased target tissue 5 alpha reductase:
    • increased other androgens:
      • exogenous eg. anabolic steroid use
      • 3 beta-hydroxysteroid deficiency (rare) ⇒ elevated DHEA levels but low testosterone levels:
        • masculinisation of females
        • hypospadias in males and precocious pseudopuberty
  • decreased oestrogen (relative androgenism in females):
    • menopause
    • anti-oestrogen Rx

male sex hormone overview:

role of kisspeptin

  • see also kisspeptin
  • Kisspeptin neurons exist in close apposition with GnRH neurons in the hypothalamus
  • Kisspeptin stimulates GnRH neurons (via Kisspeptin receptor - but may require oestradiol to work) leading to GnRH release and leads to an increase in circulating lutenizing hormone (LH) levels

role of FSH in males:

  • FSH is tropic to the Sertoli cells & with androgens maintain the gametogenic function of the testes
  • stimulates secretion of androgen binding protein & Inhibin
  • Sertoli cells:
    • secrete androgen binding protein which probably functions to maintain a high, stable supply of androgen in the tubular fluid
    • secrete inhibin which provides negative feedback on FSH secretion
    • MIS which causes regression of Mullerian ducts in males during fetal life
    • are responsible for spermatogenesis

role of LH in males:

  • LH is tropic to Leydig cells & stimulates secretion of testosterone

role of testosterone in males:

  • negative feedback on LH secretion
  • development & maintenance of secondary sex characteristics & sexual function
  • anabolic effects
  • aromatization of testosterone ⇒ oestrogen
    • stimulates growth hormone secretion ⇒ reduced fat mass

testosterone

  • principle hormone of the testes

physiology:

synthesis:

  • a C19 steroid synthesized from cholesterol via 17a-hydroxylase:
    • cholesterol ⇒
      • pregnenolone (via LH-induced c-AMP activation of protein kinase A) 
        • 17alpha hydroxylase ⇒ 17a-hydroxy-pregnenolone ⇒ DHEA ⇒ androstenedione
          • androstenedione (secreted from adrenal cortex):
            • in Leydig cells ⇒ testosterone 
              • in some target tissues via 5 alpha reductase ⇒ dihydrotestosterone (DHT)
                • the 5-alpha reductase enzyme is of 2 types:
                  • type I enzyme is found predominantly in sebaceous glands
                  • type II enzyme is found in hair follicles (and the prostate gland)
              • testosterone can be metabolised to
                • oestradiol via aromatase (forms 70% of male oestrogen)
            • in adrenal cortex:
              • ⇒ androstenedione secreted into circulation (controlled by ACTH not by LH or FSH)
                • in liver ⇒ androsterone & others (weak androgens with < 20% activity of testosterone)
              • ⇒ testosterone 

secretion:

  • Leydig cell secretion under control of LH via negative feedback on GnRH
  • small amount via adrenal cortex under control of ACTH (males & females)
  • 3 peaks of testosterone secretion:
    • testosterone secretion in males begins in fetal life with peak concentrations seen at 12 weeks of gestation. 
    • after birth there is a second peak of testosterone secretion, then, until puberty, testosterone levels are low and similar to those in girls.
    • pulsatile secretion of GnRH and LH begins at the onset of puberty and results in the maturity of the Leydig cells. 
  • in young men, there is diurnal variation in serum testosterone concentration, with the highest values seen at 8 AM and the lowest in late afternoon

bioavailability:

  • 98% of the circulating testosterone is bound to plasma proteins, the remaining 2% of free testosterone is responsible for its biological activity
  • 40% of the bound testosterone is bound to sex-hormone-binding globulin. The rest is weakly bound to albumin and is readily available to tissues when needed, hence known as “bioavailable testosterone.” 
  • the Androgen Index (100 × total testosterone/sex-hormone-binding globulin) is another measure of bioavailability.
  • DHT also circulates but at level 10% of testosterone

target organs:

  • testosterone is metabolized to dihydrotestosterone by 5-alpha reductase and to estradiol by aromatase. 
  • both DHT & testosterone bind the same receptor, however, DHT's receptor binding is more stable & thus is a way of amplifying the action of testosterone at target tissues 

metabolism:

  • most is converted into 17-ketosteroids (most are weak androgens) & excreted in urine
  • a small amount is converted into oestrogen by aromatase
  • aromatase deficiency in males results in osteoporosis

actions:

embryologic actions:

  • the presence of testis-determining factor (TDF) (produced from Y chromosome) stimulates development of Leydig cells in the 7th-8th weeks of gestation causing the cortex to regress and the medulla to develop into a testis
  • the testis secrete:
    • mullerian inhibiting factor (MIS) (via Sertoli cells):
      • inhibits development of female internal genitalia & with testosterone stimulates development of male internal genitalia
    • testosterone (via Leydig cells):
      • testosterone levels peak at 12 weeks
      • development of male internal & external genitalia
      • development of the “male” brain
      • stimulate osteoblast differentiation

neonatal actions:

  • 2nd peak of testosterone levels occur after birth
  • a neonatal dose of testosterone in female rats results in adult androgenisation & insulin resistance, thus hormonal imprinting!

adolescent/adult actions:

  • 3rd peak of testosterone levels occurs at puberty resulting in development of secondary sex characteristics
  • higher levels ⇒ androgenic effects
  • low levels in males ⇒ androgen deficiency ⇒ impotence, etc

androgenic effects:

develop & maintain male secondary sex characteristics:

  • males:
    • testosterone is necessary for libido, erectile function, and normal ejaculation
    • increased size of penis, seminal vesicles, prostate & bulbourethral glands
    • the issue of whether androgens cause prostate cancer has not been settled
    • scrotal pigmentation & rugose
    • with FSH, maintains gametogenesis
  • laryngeal enlargement ⇒ voice deeper
  • terminal hair growth:
    • male pattern hair growth - male escutcheon
    • androgenetic alopecia (prostaglandin D2 appears to have a role in mediating baldness)
  • sebaceous gland secretion thickens & increases ⇒ acne
  • more aggression
  • antidepressant properties
  • sex drive:
    • males:
      • more sexual thoughts, more sexual activity incl. masturbation which in turn produces more testosterone in men
      • negative role in attachment ⇒ marry less, more abusive in marriage, divorce more often
      • nb. testosterone levels tend to fall if attachment does occur, such as after birth of 1st baby
      • in healthy eugonadal men with erectile dysfunction, testosterone administration resulted in an increased frequency of ejaculation and masturbation, sexual desire, and sleep-related erections
    • females:
      • libido effects?

actions in embryonic females:

  • female pseudohermaphroditism 

actions in adolescent females:

  • responsible for some of the female secondary sex characteristics:
    • terminal hair growth:
      • axillary, groin hair growth
    • clitorimegaly

actions in adult females:

  • excessive levels cause androgenisation:
    • hirsutism
    • androgenetic alopecia
    • acne
    • clitorimegaly
    • insulin resistance

anabolic, growth-promoting effect

  • role in adolescent growth spurt
  • moderate sodium, potassium, water, calcium, sulphate & phosphate retention
  • increase size of kidneys

actions on bone:

  • cause fusion of epiphyses
  • inhibit the expression of interleukin-6, also known as osteoclast activating factor
  • dihydrotestosterone enhances mitogenesis in bone cells by inducing transforming growth factor beta mRNA and by enhancing the binding of insulin-like growth factor II to osteoblasts

anabolic effect on muscles:

  • muscles enlarge, shoulders broaden
  • stimulate mitosis in myoblasts by stimulating ribosomal activity and RNA polymerase synthesis
  • increased synthesis of contractile and noncontractile muscle proteins, increased intramuscular concentrations of mRNA for insulin-like growth factor I, and decreased abdominal fat mass resulting from lipolysis and decreased lipid uptake into the abdominal fat depot

haemopoietic effects:

  • androgens stimulate erythropoeisis by enhancing erythropoietin production by means of receptor-mediated transcription and by a direct effect on bone marrow
  • exogenous androgens have direct stimulatory effects on bone marrow stem cell
  • testosterone also enhances the production of heme and globin
  • androgens also increase erythropoietin production in extrarenal sources, such as in anephric patients
  • testosterone therapy has been shown to increase 2,3, diphosphoglycerate levels in the blood

lipid profile effects:

  • administration of oral non-aromatizable androgens (“anabolic steroids”), result in a significant increase in LDL cholesterol and decrease in HDL cholesterol levels. Athletes abusing high doses of these agents have an increased risk of stroke and myocardial infarction. 
  • the effects of testosterone replacement on lipids are conflicting:
    • transdermal testosterone replacement in hypogonadal men resulted in an 8% decrease in HDL cholesterol and 9% increase in total cholesterol/HDL cholesterol ratio
    • testosterone replacement in the form of gel (Andro-Gel) in hypogonadal men did not show any adverse effects on lipid profile
    • testosterone therapy has not been associated with the risk of cardiovascular events in hypogonadal elderly men

immune system effects:

  • androgens appear to reduce insidence of auto-immune disease, the beneficial effects of androgen appear to be on suppressor cells, since healthy men have a higher CD8/CD4 (suppressor/helper) ratio than do healthy women

sleep apnoea:

  • sleep apnoea syndromes are more common in men than in women
  • among women, they are more common among those who are postmenopausal
  • testosterone has been linked to the increased incidence of sleep apnoea in men:
    • increased upper airway collapsibility during sleep in a patient receiving testosterone therapy that reversed after cessation of treatment
    • testosterone administration has also been shown to blunt the central response to CO2

inhibitory feedback on pituitary LH secretion

  • and only in high doses inhibits FSH secretion
androgens.txt · Last modified: 2019/07/13 16:08 by wh