Contraceptives, HRT and SERMs Flashcards
21.10.2019
What is menopause?
- permanent cessation of menstruation
- loss of ovarian follicular activity
What is the average age menopause occurs in?
- 51
- between 45-55
Climacteric
- period of transition period
Symptoms of menopause
- hot flushes (head, neck, upper chest)
- urogenital atrophy & dyspareunia
- sleep disturbance
- loss of libido
- joint pain
-> symptoms usually diminish/disappear with time
Dyspareunia
painful sex
What is the normal HPG axis?
- pulsatile GnRH from the hypothalamus
- stimulates release of LH and FSH from the anterior pituitary
- stimulates oestradiol / inhibin production and secretion in the ovaries
- oestradiol and inhibin negatively feed back to the hypothalamus and AP
How is the HPG axis different in menopause?
Loss of ovarian follicular activity (depletion?) leads to:
- no oestradiol and inhibin production -> low oestradiol
- no negative feedback -> high LH and FSH
What are some complications of menopause?
- osteoporosis (oestrogen deficiency, loss of bine matrix, 10x increased risk of fracture)
- Cardiovascular disease (protected before menopause, same risk as men at age 70)
What is an important effect of HRT?
- controls vasomotor symptoms (hot flushes)
What are the effects of oestrogen in HRT?
- causes proliferation of the endometrium
- risk of endometrial carcinoma
What are the effects of progestogens in HRT?
- protect from increased risk of endometrial cancer
Which women would oestrogen-only HRT be recommended for?
- women post hysterectomy (basically no risk of endometrial cancer)
Why is E+P HRT generally prescribed?
- to prevent endometrial hyperplasia
What are the two main HRT formulations?
- Cyclical: E (every day) + P (12-14 days) (add P for 12-14d)
- Continuous combined
What are the different ways of administering oestrogen preparations?
- Oral estradiol (1mg)
- Oral conjugated equine oestrogen (0.625 mg)
- Transdermal (patch) oestradiol (50 microgram/day)
- Intravaginal
Oestrogens - pharmacology
- very well absorbed
- low bioavailability due to 1. pass metabolism
- groups can be added e.g. ethinyl estradiol or estrone sulphate
Estrone sulfate
“conjugated” oestrogen
Ethinyl estradiol
- The ethinyl group protects the molecule from first pass metabolism
- semi-synthetic oestrogen
- found in oral contraceptive pills
How can most oestrogen preparations be administered?
- orally
- via transdermal skin patches
What are the side effects of HRT?
- Breast cancer
- Coronary heart disease
- Deep Vein thrombosis
- Stroke
- Gallstones
Absolute risk of HRT?
The absolute risk of complications for healthy symptomatic postmenopausal women in their 50s taking HRT for five years is very low.
HRT and risk of CHD
- timing of exposure is important!!
- no excess CVD risk in younger menopausal women
- in younger women oestrogen is protective
- in older women with established atherosclerosis it is
Why does O only decrease but E+P increase the risk of CHD?
- synthetic progestins negate the protective effects of oestrogen
What are the effects of oestrogen on CHD?
- beneficial effects on lipid profile & endothelial function
Why is oestrogen harmful with regards to CHD in women >60 years of age?
- they probably have atherosclerosis
- are susceptible to prothrombotic & proinflammatory effects of oestrogen
Tibolone
- Synthetic prohormone
- Oestrogenic, progestogenic & weak androgenic actions
- Reduces fracture risk
- Increased risk of stroke (RR: 2.2)
- ? increased risk of Breast Ca
SERM
selective oestrogen receptor modulator
e.g. Raloxifene
Raloxifene
- Oestrogenic in bone: reduces risk of vertebral fractures
- Anti-oestrogenic in breast & uterus: reduces breast cancer risk
- Does not reduced vasomotor symptoms
- increased risk of VTE & fatal stroke
Tamoxifen
- anti-oestrogenic in breast tissue
- Used to treat oestrogen-dependent breast tumours & metastatic breast cancers
Premature ovarian insufficiency
Menopause occurring before the age of 40
What fraction of women are affected by premature ovarian insufficiency?
1%
What are the causes of premature ovarian insufficiency?
- chemotherapy
- radiation
- surgery
- autoimmune
What is in the combined oral contraceptive pill?
Oestrogen (ethinyl oestradiol) + Progestogen (e.g. levonorgestrel or norethisterone)
How does the oral contraceptive pill work?
- Suppress ovulation:
- E&P: negative feedback actions at hypothalamus/pituitary
- P thickens cervical mucus
Administration of COCP
Take for 21 days (or 12 weeks), stop for 7 days
When would you give a progesterone only contraceptive pill?
- in smokers
- > 35 years of age
- migraine with aura
- people with increased risk of thrombosis?
Administration of progesterone only oral contraceptive pill
Must be taken at the same time each day
- Short half-life
- Short duration of action
Long acting preparations may be given via an intra-uterine system
Name examples of emergency (post coital) contraception
- copper IUD
- levonorgestrel
- Ulipristal
Copper IUD
- exclude pregnancy first
- affects sperm viability and function
- Effectiveness not reduced in overweight/obese women
- 5 (up to 7) days after unprotected intercourse
Levonorgestrel
- efficiency reduces with time so take ASAP after unprotected sex
- within 72 hours!!
Ulipristal
- up to 120h after intercourse
- Anti-progestin activity
- delay ovulation by as much as 5 days
- Impairs implantation
