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Key concepts to be addressed

  • Benefits and risks of hormonal treatment of menopausal symptoms
  • Selective estrogen receptor modulators
  • Non-hormonal treatment of vasomotor symptoms of menopause

Revision from previous lectures

  • Foundations
    • Pharmacology 3: Receptors
  • Nuclear Receptors
    • Beginnings, Growth & Development A
    • Reproductive Pharmacology
  • Actions, adverse effects and contraindications of estrogens and progestins
    • Beginnings, Growth & Development A
    • Adrenergic Mechanisms 2
    • Storage & Release of Noradrenaline
    • α2-adrenoceptor agonists

The menopause and HRT

  • Clinical features of menopause
    • menstrual changes
    • hot flushes and night sweats
    • insomnia
    • palpitations
    • urogenital dryness
    • Mood swings

Prevalence Rates of Menopause Symptoms

  • Vasomotor = 60%
  • Sleep disturbance= 50% (linked to vasomotor)
  • Mood symptoms = 40%
  • Urinary complaints = 30%
  • Vaginal dryness = 30%

Clinical Uses of Estrogens

  • Replacement Therapy (HRT)
    • Just want to replace the hormones that are deficient due to menopause
  • Osteoporosis
  • Contraception

Physiological Actions of Estrogens

  • Amelioration of skin ageing fixes up urogenital dryness
  • Cardioprotective: premenopause, women have a lower risk of CVD than men. After menopause they catch up

Adverse Effects of Oestrogen

  • Breast tenderness
  • Uterine bleeding
  • Thrombosis
  • Endometrial hyperplasia
  • Nausea, vomiting, migraine, weight change, dizziness, liver disorders
  • Contraindications
    • Cardiovascular disease
    • History of thrombosis
    • Breast or uterine cancer
    • Liver disease

Estrogen alone or in combination with progestin

  • Estrogen alone is only prescribed to those women who have had a hysterectomy
  • Combination HRT: Estrogen + Progestin
    • Addition of progestin prevents endometrial hyperplasia and endometrial cancer

Physiological actions of Progestins

  • Female
    • Decreases estrogen mediated endometrial proliferation
    • Maintenance of pregnancy
    • Changes in endocervical glands
    • Increase in basal temperature

HRT

  • Medroxyprogesterone
  • Contraindications
    • Thromboembolic disorders
    • Cerebral vascular disease
    • Severe hepatic dysfunction
    • Breast cancer
  • Adverse effects
    • Dizziness, headache, nervousness , decreased libido, abdominal pain/discomfort, weight gain


Osteoporosis Treatment

  • Results of hormone therapy regimens on bone mineral density
  • Bone density goes up with E or E+P have higher hip+spine bone density than placebo
    • Only E in hysterectomy
  • The Women's Health Initiative (WHI) is a long-term study on strategies for preventing heart disease, breast and colorectal cancer, and osteoporotic fractures in postmenopausal women.
  • The WHI had two major parts: a randomized Clinical Trial and an Observational Study. The randomized controlled Clinical Trial (CT) enrolled 68,132 postmenopausal women between the ages of 50-79 into trials testing three prevention strategies.
  • Hormone Therapy Trials (HT):
  • Dietary Modification Trial (DM):
  • Calcium/Vitamin D Trial (CaD):
  • Problem with WHI - enrolled women into the trial who weren't on HRT; it was women who were 13 years postmenopausal (had this long period with low E)
    • If you look at a group of women which were only just entering menopause (when E levels are still high and are gradually dropping off), then there is not mortality effect
  • If you have low E for a while, you start to develop atherosclerosis. Because E was down for a while, your E receptors are less expressed. If you add E after the plaque has formed, it is problematic. If you just maintain E levels, then you decrease the risk of CVD.
  • WHI commenced therapy on average 13 years after menopause.
    • Estrogen is cardioprotective if initiated around menopause when there are still vascular estrogen receptors responsive to exogenous HRT.
    • If administered near menopause reduces progression of atherosclerotic plaques,
    • If given many years after menopause it is not beneficial and may disrupt established plaques

HRT Recommendations Post WHI

  • Initiate HRT near menopause
  • Use lower doses of hormones
  • Non-oral routes of administration for progestogens

Tibolone

  • Synthetic hormone with: estrogenic, androgenic and progestogenic properties
  • Table
  • Adverse Effects:
    • leukorrhea, abdominal pain, weight gain (water retention), vaginal bleeding, breast pain

Nuclear Receptor Signaling

  • Nuclear receptor acts as dimer: hormone binds to receptor in cytoplasm (or nucleus), binds to its brother to form a dimer; then goes into the nucleus, binds to a specific location on DNA and effects DNA transcription; this affects protein synthesis

Selective Estrogen Receptor Modulators corepressor (SERMS)

  • Normal (E):
    • E receptor has a and b subtypes
    • E binds to dimer pair of ER
    • Shape of dimer allows coactivator to bind, and it doesn't let the corepressor bind. Therefore we can initiate gene transcription
  • If you have two betas with SERM binding, then the corepressor binds, stopping initiation of transcription
  • If you have two alphas with SERM binding, then the coactivator will bind, allowing transcription
  • This allows us to select tissues that have different receptors (ie has different actions in different tissues)
    • In fact hard to find tissues that have only alpha or beta
    • What differs is the expression levels of coactivators and corepressors
    • Ie: if bind to alpha and beta receptors, too high a repressor:activator ratio may mean repression and vice versa
    • Same principle in T and P receptors

Selective Estrogen Receptor Modulators (SERMS)

The Action of SERMs depends on:

  • The expression level and ratio of ERa and ERb in the cell
  • The effect of the conformational changes induced by the SERM on binding of co-activators and co- repressors
  • The expression level and ratio of co-activator and co-reprssors in the cell

Therefore:

  • Agonist in bone (good density), brain (good mood) & liver (good lipids)
  • Antagonist in breast & endometrium
  • Estrogen sensitive breast cancer (good way to treat without ARx)
    • Tamoxifen
  • Treatment of osteoporosis
    • Raloxifene

Raloxifene

  • Contraindications
    • History of or current venous thrombosis, pregnancy, breast- feeding
  • Adverse Reactions
    • Raloxifene has been associated with increased risk of thromboembolism (risk is similar to reported risk of HRT; careful giving it many years after menopause has happened)
    • Peripheral edema, hot flashes, arthralgia , leg cramps/muscle spasm, chest pain, syncope, headache, breast pain, nausea , weight gain, abdominal pain, cough

Vasomotor Symptoms

  • HRT gives the best symptom relief, but there are lots of other risks of HRT; so sometimes we want to treat symptoms without ARx (main problematic symptom is vasomotor)

Role of Estrogen in Thermoregulation

  • Virus causes release of mediators that change your setpoint up, you feel cold and warm up to that temperature. After the mediators go, then you feel to hot and sweat to cool down.
  • E changes expression of postsynaptic 5HT receptors
  • 5HT1a = hypothermic
  • 5HT2 = hyperthermic
  • Normally there is even binding of these two types of receptors, so we get constant temperature
  • E regulates the expression of these receptors: keeps 5HT2 but loses 5HT1a receptors
  • Serotonin (from tryptophan) and NA (from tyrosine) are metabolised by MAO and stored in vesicles. An AP causes the vesicles to be released
  • NA is recycled by NET; serotonin is recycled by SERT
  • VMAT repackages the substance back into the nerve terminal
  • NA: Activating the alpha 2 adrenoceptor on presynaptic causes negative feedback on Ca in neuron and NA release
  • Serotonin: Activating the presynaptic 5HT-1a and 5-HT1B on presynaptic causes negative feedback on serotonin
  • So transporter = recycle; receptor = negative feedback
  • We could either effect the postsynaptic receptors, inhibit transporters, or inhibit receptors, or affect the metabolism of the neurotransmitter

Receptor desensitisation

  • Some classes of drugs act to increase the levels of neurotransmitters. When the receptors are bathed in very high amounts of neurotransmitter they become desensitised and the number of receptors decreases due to degradation.

GPCR Desensitisation and Internalisation

  • GRK phosphorylates the GPCR to
  • Arrestin binds to phosphorylated receptors so they bind to GPCR and stop them working. Then they're taken into a vesicle to either be recycled or degraded
    • Some receptors are preferentially recycled OR degraded, and some don't go into this system at all
  • PP = protein phosphatase, to chew off the phosphate allowing the protein to be recycled


  • Menopause treatment: bring back 5HT-1a receptors and 5HT-2 receptors are degraded; by the process above
    • This fixes thermoregulation
    • Similar to SSRIs
  • Bathe the receptors for a long time, causing degradation of the bad receptors

Selective Serotonin Reuptake Inhibitors (SSRI)

  • Paroxetine
  • Therapeutic Uses
    • Antidepressant, Vasomotor Symptoms
  • Adverse Reactions
    • Somnolence, insomnia, headache, dizziness, libido decreased, nausea, dry mouth, constipation, diarrhea

Serotonin-noradrenaline reuptake inhibitors (SNRIs)

  • Venlafaxine
  • Therapeutic Uses
    • Antidepressant, Vasomotor Symptoms
  • Adverse Reactions
    • Headache, somnolence, insomnia, dizziness, nervousness nausea, dry mouth, constipation, muscle weakness

Clonidine: a2-Adrenergic Agonist

  • Major Actions
    • Activation of presynaptic a2-AR inhibits the release of NE
  • Toxicity and Adverse Effects
    • Dry mouth & sedation Sexual dysfunction Bradycardia Hypotension
  • Therapeutic Uses
    • Systemic Hypertension
    • Vasomotor symptoms of menopause

The reason we have one drug that agonises the inhibition of release of NT and another one (SSRI) that increases NT in synapse is because the SSRI actually causes downregulation of the bad receptors.

Gabapentin

  • An analog of GABA
  • Binds to voltage-gated Ca2+ channels.
  • Acts presynaptically to decrease the release of glutamate via reduced presynaptic entry of Ca2+ via voltage- activated channels.
  • Therapeutic Uses
    • Gabapentin is effective for partial seizures and Vasomotor Symptoms
  • Adverse Reactions
    • Somnolence, dizziness, ataxia, fatigue

Deciding what to give menopausal women

  • If "No HT", can treat some of the vasomotor symptoms using one of the other drugs