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Hypothalamic-Pituitary-gonadal axis
- Hypothalamus releases gonadotropin-releasing hormone (GnRH)
- GnRH controls the release of LH and FSH
- LH and FSH cause release of androgens, estrogens and progesterone in the gonads
- A,E and P cause negative feedback to stop release of GnRH, LH and FSH
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3 Classes of anterior pituitary hormones
- Somatotropic Hormones
- Glycoprotein Hormones
- POMC-derived Hormones
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Somatotropic hormones (3)
- growth hormone
- prolactin
- placental lactogen
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Glycoprotein hormones (4)
- Luteinizing hormone
- Follicle-stimulating hormone
- Human chorionic gonadotropin
- Thyroid stimulating hormone
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POMC-derived hormones (2)
- Corticotropin
- alpha-Melanocyte stimulating hormone
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Posterior Pituitary Gland (3)
- arginine
- vasopressin
- oxytocin
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Use of Estrogens and Progestins and agonists
used for menopausal hormone therapy and contraception in women
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Use of Anti-Estrogens
Treatment of hormone-responsive breast cancer and infertillity
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Most potent naturally occuring estrogen in humans
17B-estradiol
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Estrogen Phenolic A ring
- Principle structural featur responsible for selective, high affinity binding to both receptors
- Substitutions on the A Ring will impair binding.
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Estrogen C17
Substitution of ethinyl group increases oral potency by inhiiting hepatic metabolism
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Diethylstilbestrol (DES)
- binds with high affinity to both estrogen receptors
- potent estradiol
- much longer half-life
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Biosynthesis of steroidal estrogens
- Androstenedione or testosterone aromatized by aromatase
- Reaction is catalyzed by cytochrome P450 and uses NADPH and O2 as co-substrates
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Progesterone receptor
- Favors ketone off ring at 3 position
- double bond between 4 and 5
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Synthetic Progestins
display limited binding to glucocorticoid, androgen and mineral corticoid receptors
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Non-specific progestins
lack C19 methyl group
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Gonanes
- Replace 13 methyl with 13 ethyl
- Less androgenic activity
- More potent progestin
- Inactive dextrorotary isomer and active levorotatory isomer
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Synthesis of Testosterone
Leydig cells of the testes synthesize testosterone from cholesterol
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Building block for cholesterol
- acetate
- plasma cholesterol
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Testosterone and its metabolites
- Estradiol
- Dihydrotestosterone
Effects are mediated by testosterone itself or by other metabolites.
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Glucocorticoids
- Potently suppress inflamation
- Found in creams and ointments
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coricosteroids
No need for eninyl group at C17, --OH will work because it is topical and does not need to be metabolized in the liver
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