Cholesterol and the steroid hormones part 1: structure and functions

Basic steroid structure
1. All steroid hormones based on the same 4 ring structure
  1. Cyclopentanoperhydrophenanthrene (C17)
    1. Fully saturated (no double bonds) C17 molecule
    2. Three six carbon rings (A, B, C) and one five carbon ring (D)
    3. Most natural steroids have 2 methyl (CH3) groups = C19 structure
      1. 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)
      2. This C19 steroid nucleus = androstane (all steroids are modified versions of this)
  2. Derived from cholesterol (from the diet, stores or de novo synthesis)
Steroid hormones (and vitamin D3)
1. Vitamin D3
  1. Steroid derivative
  2. Formed by action of sunlight on skin
    1. UV radiation causes the B-ring of 7-dehydrocholesterol to open
      1. = 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
2. Progestogens (C21)
  1. e.g. progesterone
  2. feature characteristic D-ring
    1. Has a ketone group [C(=O)CH3] attached at C17
  3. Receptor: Progesterone receptor (PR)
  4. Function: During the menstrual cycle and the maintenance of pregnancy
  5. Produced by: developing follicle and corpus luteum (ovary)
3. Glucocorticoids (C21)
  1. e.g. cortisol (humans); corticosterone (rodents) - parallel synthesis and difference of x1 OH group at C17
  2. Receptor: glucocorticoid receptor (GR)
  3. Function: Stress adaption
  4. Secreted by: adrenal cortex (zona fasciculata)
4. Mineralocorticoids (C21)
  1. e.g. main one = aldosterone
  2. Receptor: mineralocorticoid receptor (MR)
  3. Function: promote Na+ reabsorption in distal convuluted tubule (DCT) in the kidneys
    1. increases blood volume and pressure
  4. Secreted by: adrenal cortex (zona glomerulosa) and in a small quantity by cadiac myocytes
5. Androgens (C19)
  1. e.g. ...
    1. Testosterone - main male sex hormone
    2. Adrostenedione - features two ketone groups at C3 and C17
    3. Dihydroepiandrosterone (DHEA) - most produced steroid hormone
  2. Male sex hormones
  3. Lack side chains at C17
  4. Receptor: androgen receptor (AR)
  5. Function: male sex hormones - sexual differntiation (in utero), development of sex characteristics at puberty, libido, increased muscle and bone mass
  6. Secreted by: leydig cells (testes) - primary source; and adrenal cortex (zona reticularis) - weak androgens, e.g. DHEA
6. Oestrogens (C18)
  1. Characterised by an aromatic, phenolic A ring (alternating double, single C-bonds - with an -OH group at C3)
  2. e.g. ...
    1. Oestradiol - two -OH groups (C3 and C17)
    2. Oestrone - features a ketone group at C17
    3. Oestriol - three -OH groups (C3, C16 and C17)
  3. Receptor: Oestrogen receptor (ER)
  4. Function: Menstrual cycle (uterine development) and development of female secondary sex characteristics
  5. Secreted by: ovaries and adipose tissue
  6. Principle female sex hormones
  7. Oestrogen-like (oestrogenic) compounds
    1. ellicit response at ER, but not necessarily ture oestrogens
    2. Can be used as alternative therapies (e.g. phyto-oestrogens) in menopause
    3. Medical use:
      1. DES (diethylstilbestrol) - in advanced prostate cancer and breast cancer (in postmenopausal women)
      2. SERMS (selective ER modulators) - tissue selective (e.g. tamoxifen (Br ca), raloxifene (OP, Br ca) and femarelle (menopause))
        Used in: osteoporosis, breast cancer, menopause
    4. Problems: Can contaminate the environment and result in adverse effects in nature
      1. 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
      2. 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)

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Cholesterol and the steroid hormones part 1: structure and functions

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