Oral Contraceptives, Menopause and HRT Flashcards
What is menopause?
Permanent cessation of menstruation
- Loss of ovarian follicular activity
- Confirmed after 12 months of amenorrheoa
NOTE: The average age is 51 years (age range: 45-55)
What is the term given to the period of transition just before menopause? Describe this period of transition.
Climacteric period
- Normal cycles → irregular cycles (oligomenorrhoea) → amenorrhoea
- So essentially the irregular cycles are charactertistic of the climacteric period
State some symptoms of menopause.
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Hot flushes (vasomotor symptoms)
- Sudden feelings of heat that spread through head, neck and upper chest
- Drop in oestrogen leads to hormonal imbalance and disruption in thermoregulation
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Urogenital atrophy
- leads to dyspareunia = difficult or painful sexual intercourse
- Lack of oestrogen causes thinning of vaginal walls and drying of secretions as these are maintained by oestrogen
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Lack of oestrogen also affects bladder control:
- Lining of your urethra, the tube that empties urine from your bladder, begins to thin.
- Pelvic floor muscles, which support urethra and bladder, weakens.
- Sleep disturbance
- Can be due to hot flushes
- Lack of oestrogen causes hormonal imbalance which can affect melatonin levels and impact sleep
- Decreased libido (sex drive)
- Depression
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Decline in oestrogen leads could affect NT levels in the brain
- Oestrogen enhances levels of NA, serotonin, dopamine which influence mood
- Sleep disturbance would also affect mood
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Decline in oestrogen leads could affect NT levels in the brain
- Joint pain
- Oestrogen is responsible for regulating fluid levels in the body
- Low oestrogen meansbody becomes less able to hold water
- This can affect the hydration and lubrication of the joint tissues, including the cartilage, ligaments and tendons
- This reduces flexibility of joints causing stiffness
- Less lubrication and more friction can lead to tissue damage causing pain and inflammation
What do the ovaries produce that feeds back on the HPG axis?
Oestradiol and Inhibin B
- These inhibit LH and FSH from the anterior pituitary AND GnRH from the hypothalamus
How does this feedback change in menopause?
- There is a loss of ovarian follicular activity so you get a decreased production of oestradiol and inhibin B
- This means that there is less negative feedback on the HPG axis
- Therefore, you get an increase in LH and FSH levels
NOTE: You wouldn’t really get an increase in GnRH as LH and FSH would be inhibiting GnRH release by negative feedback
What are the main complications of menopause?
Osteoporosis
- Oestrogen has anabolic effects on bone
- Therefore, oestrogen decline leads to loss of bone density
- This makes bones more brittle and prone to fracture
Cardiovascular disease
- Women are protected against cardiovascular disease before menopause
- Effects of oestrogen on the circulatory sytem are protective against CVD
- They have the same risk as men by the age of 70
What is HRT primarily for?
The control of vasomotor symptoms = hot flushes
- Temperature regulation is often linked to constriction/dilation of blood vessels (i.e. vasomotor)
What are the risks of giving oestrogen as part of HRT?
Endometrial hyperplasia → increases the risk of endometrial carcinoma
- Oestrogen stimulates thickening of endometrium
- Hyperplasia = increase in cell number
- This would be due to increased cell division so the cell cylce regulation is already a bit off which means it is more prone to become completely dysregulated by a mutation (cancerous state)
How is this effect of oestrogen prevented?
You give progesterone as well as oestrogen
- The progesterone blocks this effect of oestrogen on the endometrium and, hence, prevents endometrial hyperplasia
- Progesterone has anti-mitogenic effects (i.e. ani-mitosis), so counteracts the mitogenic effects of oestrogen
In which subset of patients would you give oestrogen only HRT?
Patients who have had a hysterectomy
- There is no uterus so there is no risk of oestrogen stimulating endometrial hyperplasia (i.e. no endometrium to be stimulated)
Describe the 2 different formulations of HRT.
Cyclical:
- Take oestogen every day
- Then for the last 12-14 days you take progesterone
Combined continuous
- Take oestrogen and progesterone together every day
State 4 different types of oestrogen preparations.
- Oral oestradiol (1 mg)
- Oral conjugated equine oestradiol (0.625 mg)
- Transdermal (i.e. patch) oestradiol (50 mcg/day)
- Intravaginal
What are the different types of oestrogens?
- Oestradiol
- Oestrone sulphate (‘conjugated’ oestrogen)
- Ethinyl oestradiol
The first two are produced endogenously
Ethinyl oestradiol is semi-synthetic (i.e. formed by the chemical conversion a naturally occurring product - here oestradiol)
Describe the absorption and metabolism of oestradiol.
- Oestradiol is absorbed well
- However, it has high first pass metabolism so has low bioavailability
- This means that in oral preparations, you must give a high dose of oestradiol
NOTE: Most oestrogens can be administered via transdermal skin patches as well as orally - direct into systemic circulation to overcome problem of first pass metabolism with oral administration
Name a semi-synthetic oestrogen that’s used in oral contraceptives.
Ethinyl oestradiol
- The ethinyl group protects the drug from first pass metabolism
- Therefore lower dose needed to be administered orally, as bioavailability of this drug is higher - i.e. a greater proportion of the active drug ends up in the systemic circulation
State some side-effect/risks of HRT.
- Breast cancer
- Coronary heart disease
- Deep Vein thrombosis
- Stroke
- Gallstones
NOTE: The absolute risk of complications for healthy symptomatic postmenopausal women in their 50s taking HRT for five years is very low.
How does HRT affect coronary heart disease risk?
Increased risk of CHD events in women taking HRT
- Women’s Health Initiative trials
- 19 additional events/yr per 10,000 women
- Mean age of CHD onset: 63 years
But timing of exposure is important
- No excess risk in younger menopausal women
- Women < 10 years since menopause or 50-59 years: no excess risk
HRT type is also important
- Increased risk with oestrogen & progesterone
- Decreased risk with oestrogen only
Describe the effects of oestrogen and progesterone in terms of HRT and CHD.
Oestrogen:
- Has beneficial effects on lipid profile and endothelial function
- Increases HDL levels and increasing LDL level
Synthetic progestins:
- Negate these effects of estrogen
- Endogenous progesterone doesn’t have this negating effect - has a neutral effect
- However, progestin has a slightly different structure to progesterone - has androgenic properties
- This then leads to negation of the effects of oestrogen on lipoprotein metabolism
Older women (>60):
- Susceptible to prothrombotic & proinflammatory effects of oestrogen
- So you get a switch in oestrogenic effects with ageing - anti- → proinflammatory/thrombotic
- Makes sense as ageing comes with a lot of changes
- This can lead to atherosclerosis
Name a synthetic prohormone and describe its effects.
Tibolone
Effects:
- Oestrogenic
- Progestogenic
- Weak androgenic
NOTE:
- Tibolone is a pro-drug so form metabolites which then exert and effect
- Different metabolites of tibolone exert these different effects
What are the risks and benefits of tibolone?
Benefit:
- Reduced fracture risk
Risk:
- Increased risk of stroke
- Due to pro-thrombotic effects of oestrogen with ageing (increased DVT risk with HRT → stroke)
- Increased risk of breast cancer maybe
What is raloxifene and how does it work?
It is a selective oestrogen receptor modulator (SERM)
In bone it has oestrogenic effects and reduces the risk of fracture In breast and uterus it has anti-oestrogenic effects and reduces the risk of breast cancer
What are the problems with raloxifene?
It is associated with an increased risk of fatal stroke and VTE
What is tamoxifen?
Anti-oestrogenic on breast tissue
What is tamoxifen used for?
Treatment of oestrogen-dependent breast tumours and metastatic breast cancers
What is the term given for menopause before the age of 40?
Premature Ovarian Insufficiency
What could POI be caused by?
Autoimmune Surgery Chemotherapy Radiotherapy
What type of oestrogen is in the combined oral contraceptive pill?
Ethinyl oestradiol
What types of progestogen is used in the combined oral contraceptive pill?
Levonorgestral Norethistrone
What other effect do progestogens have that reduces the chance of conception?
It thickens cervical mucus meaning that it is more difficult for sperm to penetrate it
When would you use the progesterone only pill?
If oestrogen is contraindicated – this is if there is an increased risk of thrombosis (oestrogen has pro-coagulant effects)
What is an important point to remember about when to take the progesterone only pill?
It must be taken at the same time every day
What is the name given to the long-acting intra-uterine progesterone device?
Mirena
What 3 things can you use for emergency (post-coital) contraception?
Copper IUD (affects sperm viability and function and inhibits fertilisation) Levonorgestral (within 72 hours – high dose progesterone) Ulipristal (within 120 hours) Anti-progestin activity Delays ovulation by as much as 5 days Impairs implantation
