L01 - The HPG Axis

Hypothalamus
1. Found at the base of the brain, between the midbrain and forebrain
2. Collection of brain nuclei/centres
3. Controls endocrine function via pituitary gland
4. Gonadotrophin releasing hormone (GnRH)
  1. Short-life peptide
  2. Pulsatile GnRH secretion at puberty triggers gonad activation
  3. Continuous secretion leads to down regulation of GnRH receptors on gonadotroph cells
    1. Causes lack of LH/FSH release
  4. Can block GnRH effects using antagonist or agonist (due to resulting downregulation of receptors)
Pituitary Gland
1. Pea-sized gland at the base of the brain
2. Hormone secretion regulated by thalamus and by feedback loops from circulating hormones
3. Anterior pituitary hormones in reproduction
  1. Gonadotrophins
    1. FSH
      1. Secreted by gonadotroph cells (ant. pit.)
      2. Acts on sertoli (testes) and granulosa (ovary) cells
      3. Has an alpha chain, a beta chain and two carbohydrate chains
      4. Receptor LHCGR
    2. LH
      1. Secreted by gonadotroph cells (ant. pit.)
      2. Acts on leydig, theca and granulosa cells
      3. Has an alpha chain, a beta chain and a carbohydrate chain
      4. Receptor LHCGR
    3. hCG
      1. Human corionic gonadotrophin
        Secreted by trophoblast cells
        Acts of luteal cells in the corpus luteum
        Has an alpha chain, a beta chain and two carbohydrate chains
        FSHR
    4. Bind to cell surface receptors and signal via G-proteins
  2. Proteins and Peptides
    1. ACTH - corticotrophs
    2. GH - somatotrophs
    3. Prolactin - lactotrophs
4. Communication
  1. Direct - neural to post. pit.
  2. Indirect - vascular to ant. pit.
    1. GnRh produces in parvocellular neurons and travels to ant.pit. in portal blood
      1. Stimulates FSH and LH production
  3. Hypophyseal portal system
Gonads
1. Different for males and females
  1. Sex steroids and regulatory factors produced
    1. Sex steroids
      1. Progestagens
        Pregnancy
        Progesterone
        17alpha-OHP
        20alpha-OHP
        Functions
        Preparation of the uterus
        Maintenance of the uterus during pregnancy
        Growth of mammary glands
        Suppression of lactation
        Catabolic effects
        Regulation of gonadotrophins
        Receptors
        PR-A
        PR-B
      2. All derived from cholesterol
      3. Androgens
        Male
        DHT
        Testosterone
        Androstenedione
        DHEA
        Functions
        Development and maintenance of the male reproductive system
        Secondary sexual characteristics
        Sexual function
        Support spermatogenesis
        Regulation of gonadotrophins
        Receptors
        AR - polymorphic with differing sensitivites to androgens
      4. Oestrogens
        Female
        Oestradiol 17beta
        Puberty to menopause
        Oestriol
        Pregnancy
        Oestrone
        Post-menopause
        Functions
        Secondary sexual characteristics
        Stimulate growth and activity of mammary glands
        Stimulation proliferation of endometrium for progesterone action
        Regulate gonadotrophins
        Receptors
        ERalpha
        ERbeta
      5. Lipid soluble, act via steroid response elements (SREs)
      6. Bound to carrier proteins
        Albumin
        Sex hormone binding globulin (SHBG)
        Androgen binding protein (ABP)
      7. Steroid action
        Potency
        Depends on affinity of steroid to receptor
        Varies within each class
        Cross-occupancy
        Some bind receptors from other classes
        Side-effects result
        Some bind but don't activate
        Antagonists
        Regulation
        Alter amount of steroid produced
        Regulated by and regulate gonadotrophins of ant. pit.
        Feedback loops
        Alter amount or structure of receptor
        Important in reproduction - gives better picture than hormone levels
  2. Negative feedback in males, complicated feedback in females
Clinical aspects
1. Fertility
  1. For females, endocrine problems are a common cause of infertility
2. Central Hypogonadism
  1. Hypothalamus/pituitary problem
  2. Low FSH/LH
3. Primary Hypogonadism
  1. Ovary/testes problem
  2. Lack of feedback
  3. High FSH/LH
4. Prolactin
  1. Inhibits HPG axis when in high doses
  2. Levels increase in pregnancy and breast feeding
  3. Inhibits gonadal activity through central suppression of GnRH
  4. Induces lactational amenorrhea
5. The Menstrual Cycle
  1. Cyclic gametogenesis, once per month
  2. Hormonal changes cause folliculogenesis and endometrium changes
  3. Three phases
    1. Follicular/proliferative
    2. Ovulation
    3. Luteal/secretory
  4. Duration
    1. 26-32 days
      1. Follicular phase varies
    2. Luteal phase
      1. 14 days
    3. Fertile period
      1. Oocyte - 24 hours
      2. Sperm - 5 days
      3. Oligomenorrhea
        <9 cycles in last 12 months
      4. Amenorrhea
        No bleed in 6 months
        Primary - since birth
        Secondary - ceased
  5. Menopause
    1. Females - finite number of oocytes
      1. Ovulation ceases around 50
        Lack of progesterone/oestrogen production by ovary
    2. Removal of -ve feedback leads to high FSH/LH levels
      1. Higher FSH closer to menopause
  6. Test for ovulation on day 21
6. Treatments/uses
  1. Hormonal contraception
    1. Synthetic progestagens and oestrogens
      1. Suppress ovulation
      2. Thickens cervical mucous
      3. Thins endometrium
  2. Fertility treatment
    1. IVF/ICSI
    2. Down-regulate HPG axis with GnRH agonist/antagonist, stimulate with FSH, induce oocyte maturation with hCG
  3. Prostate cancer treatment
    1. GnRH agonists suppress T cell production

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L01 - The HPG Axis

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	Erstellt von chris.brees vor fast 11 Jahre