Cholesterol and the steroid hormones part 1: structure and functions

Cholesterol and the steroid hormones part 1: structure and functions

1. Basic steroid structure

   • All steroid hormones based on the same 4 ring structure
     • Cyclopentanoperhydrophenanthrene (C17)
       • Fully saturated (no double bonds) C17 molecule
       • Three six carbon rings (A, B, C) and one five carbon ring (D)
       • Most natural steroids have 2 methyl (CH3) groups = C19 structure
         • Numbering (CH3 groups: on C13 = "C18" and C10 = "C19")
           • 1 (A)
             • 2 (A)
               • 3 (A)
                 • 4 (A)
                   • 5 (A/B)
                     • 6 (B)
                       • 7 (B)
                         • 8 (B/C)
                           • 9 (B/C)
                             • 10 (A/B)
                               • 11 (C)
                                 • 12 (C)
                                   • 13 (C/D)
                                     • 14 (C/D)
                                       • 15 (D)
                                         • 16 (D)
                                           • 17 (D)
         • This C19 steroid nucleus = androstane (all steroids are modified versions of this)
     • Derived from cholesterol (from the diet, stores or de novo synthesis)

2. Steroid hormones (and vitamin D3)

   • Vitamin D3
     • Steroid derivative
     • Formed by action of sunlight on skin
       • UV radiation causes the B-ring of 7-dehydrocholesterol to open
         • = cholecalciferol
           • Undergoes first hydroxylation in the liver at C25
             • Second hydroxylation in the kidney at C1 = 1, 25 dihydroxycholecalciferol
               • (Active vitamin D3)
                 • Acts on the vitamin D receptor (intracellular)
                   • Receptor forms transcription complex and plays a major role in calcium metabolism
   • Progestogens (C21)
     • e.g. progesterone
     • feature characteristic D-ring
       • Has a ketone group [C(=O)CH3] attached at C17
     • Receptor: Progesterone receptor (PR)
     • Function: During the menstrual cycle and the maintenance of pregnancy
     • Produced by: developing follicle and corpus luteum (ovary)
   • Glucocorticoids (C21)
     • e.g. cortisol (humans); corticosterone (rodents) - parallel synthesis and difference of x1 OH group at C17
     • Receptor: glucocorticoid receptor (GR)
     • Function: Stress adaption
     • Secreted by: adrenal cortex (zona fasciculata)
   • Mineralocorticoids (C21)
     • e.g. main one = aldosterone
     • Receptor: mineralocorticoid receptor (MR)
     • Function: promote Na+ reabsorption in distal convuluted tubule (DCT) in the kidneys
       • increases blood volume and pressure
     • Secreted by: adrenal cortex (zona glomerulosa) and in a small quantity by cadiac myocytes
   • Androgens (C19)
     • e.g. ...
       • Testosterone - main male sex hormone
       • Adrostenedione - features two ketone groups at C3 and C17
       • Dihydroepiandrosterone (DHEA) - most produced steroid hormone
     • Male sex hormones
     • Lack side chains at C17
     • Receptor: androgen receptor (AR)
     • Function: male sex hormones - sexual differntiation (in utero), development of sex characteristics at puberty, libido, increased muscle and bone mass
     • Secreted by: leydig cells (testes) - primary source; and adrenal cortex (zona reticularis) - weak androgens, e.g. DHEA
   • Oestrogens (C18)
     • Characterised by an aromatic, phenolic A ring (alternating double, single C-bonds - with an -OH group at C3)
     • e.g. ...
       • Oestradiol - two -OH groups (C3 and C17)
       • Oestrone - features a ketone group at C17
       • Oestriol - three -OH groups (C3, C16 and C17)
     • Receptor: Oestrogen receptor (ER)
     • Function: Menstrual cycle (uterine development) and development of female secondary sex characteristics
     • Secreted by: ovaries and adipose tissue
     • Principle female sex hormones
     • Oestrogen-like (oestrogenic) compounds
       • ellicit response at ER, but not necessarily ture oestrogens
       • Can be used as alternative therapies (e.g. phyto-oestrogens) in menopause
       • Medical use:
         • DES (diethylstilbestrol) - in advanced prostate cancer and breast cancer (in postmenopausal women)
         • SERMS (selective ER modulators) - tissue selective (e.g. tamoxifen (Br ca), raloxifene (OP, Br ca) and femarelle (menopause))
           • Used in: osteoporosis, breast cancer, menopause
       • Problems: Can contaminate the environment and result in adverse effects in nature
         • e.g. oestrogenic compounds from industrial compounds (dicofol or DDT -> DDE when metabolised)
           • DDE is oestrogenic
           • e.g. alligators in lake Apopka (reduced fertility, fewer hatching eggs, small peninses and dysfunctional reproductive organs in the young
         • In humans?
           • Some evidence of increased incidence of problems with male fertility and in utero development....
             • Falling sperm count
             • Increased numbers of; hypospadias (underdeveloped penis - urethra opening along the length of the penis) and cryptorchidism (undescended testes)