Menopause, HRT and oral contraceptive

Question 1

Why can’t we measure GnRH

Answer 1

It’s not in the peripheral circulation

Question 2

What is a common symptom of menopause

Answer 2

Sleep Disturbance

Question 3

What may be some of the patient worries regarding HRT and menopause

Answer 3

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

Question 4

Define menopause

Answer 4

Permanent cessation of menstruation
Loss of ovarian follicular activity
They stop making estradiol

Question 5

What are the key features of menopause

Answer 5

Average age 51 (range 45-55)

Climacteric: period of transition period- periods become irregular until they eventually stop.

Question 6

How do some women view menopause

Answer 6

This is a natural process of life.

The body at the beginning will get a bit mad.

Question 7

Describe the eventual transition to menopause

Answer 7

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

Question 8

State the symptoms of menopause

Answer 8

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.

Question 9

What do the ovaries produce that has feedback on the HPG axis

Answer 9

Oestradiol and Inhibin B

Negative feedback at the level of the anterior pituitary and the hypothalamus.

Question 10

Describe the hormonal changes in menopause

Answer 10

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.

Question 11

Describe how oesteoporosis is a key complication of menopause

Answer 11

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).

Question 12

Describe cardiovascular disease as a key complication of menopause

Answer 12

protected against CVD before the menopause

have the same risk as men by the age of 70

Question 13

What is the key aim of HRT

Answer 13

Control vasomotor symptoms (hot flushes) - which are very problematic for paitents- major disruption to their life.

Question 14

Summarise the basis of HRT that should be given to post-menopausal women

Answer 14

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

Question 15

Describe the basis of HRT is the woman has had a hysterectomy

Answer 15

(If hysterectomy: E only)

No endometrium, thus no risk of endometrial cancer.

Question 16

Describe two common HRT formulations

Answer 16

can be cyclical, with oestrogen daily and progesterone every two weeks, or continuous combined

Question 17

Describe the different oestrogen preparations

Answer 17

Oral estradiol (1mg)
Oral conjugated equine oestrogen (0.625 mg)
Transdermal (patch) oestradiol (50 microgram/day)
Intravaginal

Question 18

Describe the absorption and metabolism of estradiol

Answer 18

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

Question 19

Describe some different preparations of estradiol

Answer 19

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.

Question 20

What can most oestrogens be administered as

Answer 20

Most oestrogens can also be administered via transdermal skin patches

Question 21

State some of the side effects of HRT

Answer 21

Breast cancer
Coronary heart disease
Deep Vein thrombosis
Stroke
Gallstones

Question 22

What is the key difference between the doses of oestrogen given in HRT and the doses in oral contraceptives

Answer 22

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.

Question 23

What is important to remember regarding the absolute risk of HRT complications

Answer 23

The absolute risk of complications for healthy symptomatic postmenopausal women in their 50s taking HRT for five years is very low.

Question 24

What are the take home messages form the WHI trials

Answer 24

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

Question 25

Describe and explain the results from the WHI trials

Answer 25

``` 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. ```

Question 26

Describe tiobolone

Answer 26

Synthetic prohormone Oestrogenic, progestogenic & weak androgenic actions Reduces fracture risk Increased risk of stroke (RR: 2.2) ? increased risk of Breast Ca

Question 27

Which property of oestrogen receptors do SERMs exploit

Answer 27

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.

Question 28

Describe raloxifene

Answer 28

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

Question 29

What is tamoxifen

Answer 29

Anti-oestrogenic on breast tissue Used to treat oestrogen-dependent breast tumours & metastatic breast cancers But Oestrogenic effects on bone

Question 30

Summarise premature ovarian insufficiency

Answer 30

Menopause occurring before the age of 40 1% of women Autoimmune Surgery Chemotherapy Radiation The last 3 are iatrogenic

Question 31

When is raloxifene used

Answer 31

Used for treatment & prevention of postmenopausal osteoporosis

Question 32

Describe the absorption and metabolism of progestogerones

Answer 32

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.

Question 33

Describe combined oral contraceptives

Answer 33

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

Question 34

Describe the key features of combined oral contraceptives

Answer 34

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

Question 35

What is the effect of oestrogen on weight

Answer 35

Increased weight (water retention and fat deposition)

Question 36

When is the progesterone only contraceptive indicated

Answer 36

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).

Question 37

When should progesterone only contraceptives be given

Answer 37

Must be taken at the same time each day Short half-life Short duration of action

Question 38

Describe some longer-lasting preparations of progesterones

Answer 38

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

Question 39

Describe the morning after pill

Answer 39

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

Question 40

Describe copper IUD as emergency contraception

Answer 40

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

Question 41

Describe urilipristal as emergency contraception

Answer 41

(up to 120 hours after intercourse) Anti-progestin activity delay ovulation by as much as 5 days Impairs implantation