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.
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
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
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:
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