Menopause, HRT and oral contraceptive Flashcards
Why can’t we measure GnRH
It’s not in the peripheral circulation
What is a common symptom of menopause
Sleep Disturbance
What may be some of the patient worries regarding HRT and menopause
Bones- damaging effects of menopause on the bone (loss of bone density) Breast cancer (side effects of HRT) ‘Blood clots in the leg’ Stroke ‘Heart attack’- CVS effects of HRT
Define menopause
Permanent cessation of menstruation
Loss of ovarian follicular activity
They stop making estradiol
What are the key features of menopause
Average age 51 (range 45-55)
Climacteric: period of transition period- periods become irregular until they eventually stop.
How do some women view menopause
This is a natural process of life.
The body at the beginning will get a bit mad.
Describe the eventual transition to menopause
Climacteric period
You go from having normal regular cycles and then it becomes a little irregular (oligomenorrhoea) and then it progresses to amenorrhoea.
Permanent cessation of menstruation - amenorrhoea for more than 12 months
State the symptoms of menopause
Hot flushes (head, neck, upper chest) Urogenital atrophy & dyspareunia (pain having sexual intercourse)
Sleep disturbance
Depression
Decreased libido
Joint pain
Symptoms usually diminish/disappear with time.
What do the ovaries produce that has feedback on the HPG axis
Oestradiol and Inhibin B
Negative feedback at the level of the anterior pituitary and the hypothalamus.
Describe the hormonal changes in menopause
The ovaries no longer produce estradiol and inhibin B
Hence, less negative feedback on the anterior pituitary and the hypothalamus
High GnRH, high LH and high FSH.
Describe how oesteoporosis is a key complication of menopause
Oestrogen deficiency
Loss of bone matrix
10-fold increased risk of fracture
§ Loss of 1-3% of bone mass/year and have 10x increase risk of fracture.
Lose anabolic effects of oestrogen on bone (via osteoblasts).
Describe cardiovascular disease as a key complication of menopause
protected against CVD before the menopause
have the same risk as men by the age of 70
What is the key aim of HRT
Control vasomotor symptoms (hot flushes) - which are very problematic for paitents- major disruption to their life.
Summarise the basis of HRT that should be given to post-menopausal women
Oestrogen (E):
endometrial proliferation
risk of endometrial carcinoma
Progestogens (P)- sheds endometrial lining- thus reducing the risk of endometrial cancer
HRT: E + P to prevent endometrial hyperplasia
Describe the basis of HRT is the woman has had a hysterectomy
(If hysterectomy: E only)
No endometrium, thus no risk of endometrial cancer.
Describe two common HRT formulations
can be cyclical, with oestrogen daily and progesterone every two weeks, or continuous combined
Describe the different oestrogen preparations
Oral estradiol (1mg)
Oral conjugated equine oestrogen (0.625 mg)
Transdermal (patch) oestradiol (50 microgram/day)
Intravaginal
Describe the absorption and metabolism of estradiol
Oestradiol is absorbed well but it is heavily metabolised in the liver (first pass) so the bioavailability is very low.
This means that in oral preparations, you must give a high dose of oestradio
Describe some different preparations of estradiol
Estrone sulphate (‘conjugated’ oestrogen)
Ethinyl estradiol :a semi-synthetic oestrogen
The ethinyl group protects the molecule from first pass metabolism- core part or oral contraceptives.
What can most oestrogens be administered as
Most oestrogens can also be administered via transdermal skin patches
State some of the side effects of HRT
Breast cancer Coronary heart disease Deep Vein thrombosis Stroke Gallstones
What is the key difference between the doses of oestrogen given in HRT and the doses in oral contraceptives
In HRT you are just giving a little bit of oestrogen to prevent the symptoms of menopause.
In contraception, you are trying to suppress the HPG axis so you give a more potent type of oestrogen.
What is important to remember regarding the absolute risk of HRT complications
The absolute risk of complications for healthy symptomatic postmenopausal women in their 50s taking HRT for five years is very low.
What are the take home messages form the WHI trials
Increased risk of CHD events!
19 additional events/yr per 10,000 women
Mean age: 63 years
Timing of exposure is important
No excess risk in younger menopausal women
Women < 10 years since menopause or 50-59 years: no excess risk
Describe and explain the results from the WHI trials
Additional cases per 1000 women (compared to oestrogen alone) taking combined (E+P) HRT for 5 years:
Breast cancer (invasive): 3
CHD: 2.5
DVT: 5
Stroke: 2.5
However both are protective against all cause mortality.
When you are young:
Oestrogen:
beneficial effects on lipid profile &
endothelial function
Synthetic progestins:
Negate these effects of estrogen
Over 60 Atherosclerosis Susceptible to prothrombotic & proinflammatory effects of oestrogen Hence the increased risk of CHD in this study.
Describe tiobolone
Synthetic prohormone
Oestrogenic, progestogenic & weak androgenic actions
Reduces fracture risk
Increased risk of stroke (RR: 2.2)
? increased risk of Breast Ca
Which property of oestrogen receptors do SERMs exploit
They have different structures at different sites in the body- allowing SERMs to have agonistic effects at some sites, but antagonistic effects at other sites.
Describe raloxifene
Selective oestrogen receptor modulator
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
What is tamoxifen
Anti-oestrogenic on breast tissue
Used to treat oestrogen-dependent breast tumours & metastatic breast cancers
But Oestrogenic effects on bone
Summarise premature ovarian insufficiency
Menopause occurring before the age of 40
1% of women
Autoimmune
Surgery
Chemotherapy
Radiation
The last 3 are iatrogenic
When is raloxifene used
Used for treatment & prevention of postmenopausal osteoporosis
Describe the absorption and metabolism of progestogerones
Progesterone is poorly absorbed and rapidly metabolised in the liver.
Progesterone can be given by intramuscular injection as a depot preparation.
A variety of orally active synthetic progestogens are available e.g. norethisterone.
Describe combined oral contraceptives
Oestrogen (ethinyl oestradiol) + Progestogen (e.g. levonorgestrel or norethisterone)
Suppress ovulation:
E&P: negative feedback actions at hypothalamus/pituitary
P thickens cervical mucus (makes it harder for sperm to fertilise the egg)
Take for 21 days (or 12 weeks), stop for 7 days
Describe the key features of combined oral contraceptives
Combination of an oestrogen (ethinyl oestradiol) and a progestogen (e.g. levonorgestrel or norethisterone) provides synergistic pharmacology to suppress ovulation via multiple mechanisms:
E upregulates P receptors.
E counteracts the androgenic effects of synthetic P
What is the effect of oestrogen on weight
Increased weight (water retention and fat deposition)
When is the progesterone only contraceptive indicated
When oestrogens contra-indicated
smoker, > 35 yrs old, migraine with aura
e.g. CVS problems, history of thrombosis, prior to major surgery, during lactation (oestrogen should be low during lactation).
When should progesterone only contraceptives be given
Must be taken at the same time each day
Short half-life
Short duration of action
Describe some longer-lasting preparations of progesterones
Long acting preparations may be given by deep intramuscular injection (e.g. medroxyprogesterone acetate/Depot-Provera) or via an intra-uterine system (Mirena)
Oral (‘POP’) preparations -progersterone only pill
Describe the morning after pill
Combined E & P or P only (levonorgestrel)
2 doses 12 hours apart, beginning as soon as possible within 72 hours of intercourse; single one-step double strength tablet also available.
May cause nausea and vomiting
Describe copper IUD as emergency contraception
Copper IUD (intrauterine contraceptive device)
exclude pregnancy first
affects sperm viability and function- thus preventing fertilisation
Effectiveness not reduced in overweight/obese women
5 (up to 7) days after unprotected intercourse
Describe urilipristal as emergency contraception
(up to 120 hours after intercourse)
Anti-progestin activity
delay ovulation by as much as 5 days
Impairs implantation
