STRUCTURE OF STEROID HORMONES



STRUCTURE OF STEROID HORMONES

•        All steroids have a basic perhydrocyclopentanephenanthrene molecule

•        Has three 6-carbon rings and one 5-carbon ring

•        One ring is benzene, two rings naphthalene and three rings phenanthrene - the 5-carbon ring is cyclopentane

•        Divided into three groups according to the number of carbon atoms:

1) 21 - carbon series: Includes corticosteroids and progestins - the basic structure is the pregnane nucleus

2) 19-carbon series: Includes all androgens and the basic structure is the androstane nucleus

3) 18-carbon series: Includes oestrogens - estrange nucleus

•        All derived from cholesterol (27 carbons) which is converted to pregnanes (21C) to androstanes (19C) and then to estranges (18C)

STEROID SYNTHESIS

•        CHOLESTEROL TO PREGNENOLONE: Occurs by hydroxylation within the mitochondria

•        Tropic hormones from the pituitary increase cholesterol uptake and hydroxylation

•        Most of the cholesterol used is from mobilisation of intracellular stores

•        The rate limiting step in steriodogenesis is the transfer of cholesterol from the outer to the inner mitochondrial membrane

•        Long-term stimulation of steroid synthesis requires protein synthesis while acute stimulation occurs independent of new mRNA synthesis

•        PREGNENOLONE TO PROGESTERONE: Catalysed by 3-beta hydroxylsteroid dehydrogenase which exists in 2 isoforms, types I & II, two separate gene products on chromosome I

•        The type II gene is expressed in the gonads and adrenal gland

•        PROGESTERONE TO 17-alpha-hydroxy PROGESTERONE - the immediate precursor of the C19 androgens

•        PREGNENOLONE can also be directly converted to DEHYDROEPIANDROSTERONE (DHEA)

•        Both 17-alpha HYDROXYPROGESTERONE & DHEA can be converted to ANDROSTENDIONE (C19)

•        ANDROSTENDIONE is converted to TESTOSTERONE by 17-beta hydroxysteroid dehydrogenase

•        Both C19 steroids (androstendione and testostereoe) are readily converted to the C18 steroid OESTROGEN (oestradiol ans oestrone) by aromatisation which occurs in the smooth endoplasmic reticulum

•        The reactions converting pregnenolone and progesterone to 17-hydroxylated products occur in the smooth endoplasmic reticulum

•        There are 2 human 21-hydroxylase genes on chromosome 6, the A & B genes - only the B gene is active

•        17-beta-HYDROXYSTEROID DEHYDROGENASE (non-P450 enzyme, as is 5-alpha reductase)- converts oestrone to oestradiol, androstendione to testosterone and dehydroepiandrosterone to androstendiol and vice versa - the enzyme has four isoforms

•        Type I - avtive in placenta: oestrone to oestradiol

•        Types II & IV - testosterone to androstendione; oestradiol to oestrone

•        Typt II - active in testis, converts androstendione to testosterone

STEROID HORMONE TRANSPORT

•        Circulate bound to albumin, sex hormone binding globulin and corticosteroid binding globulin

•        Only a small proportion is free and biologically active

•        Hyperthyroidism, pregnancy and oestrogen administration increase SHBG concentrations

•        Corticosteroids, androgens, growth hormone, insulin, progesterone and IGF-I decrease SHBG concentrations

•        Circulating levels of SHBG are inversely related to weight

•        SHBG concebtrations are a marker of hyper-insulinaemic insulin resistance

 

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