androgens

see also:

• oestrogens
• progestogens
• anabolic steroids
• androgen deficiency, the male menopause, etc
• 2025: Review article: Testosterone and men's health: An in-depth exploration of their relationship

• androgens are substances that directly result in androgenic effects

• 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:
      • progestogens
      • polycystic ovary syndrome
      • androgenetic alopecia?
      • puberty (males & females)
  • increased conversion from testosterone via increased target tissue 5 alpha reductase:
    • androgenetic alopecia
  • 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

• 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

• follicle stimulating hormone (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

• luteinizing hormone (LH) is tropic to Leydig cells & stimulates secretion of testosterone

• 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

• principle hormone of the testes

• 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 

• Leydig cell secretion under control of luteinizing hormone (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 luteinizing hormone (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

• 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

• 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 

• 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

• 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

• 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!

• 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

• 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?

• female pseudohermaphroditism 

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

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

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

• 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

• 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

• 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

• 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

• 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 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

• and only in high doses inhibits FSH secretion