Contraceptives, HRT and SERMs

Question 1

What is menopause?

Answer 1

• permanent cessation of menstruation

- loss of ovarian follicular activity

Question 2

What is the average age menopause occurs in?

Answer 2

• 51

- between 45-55

Question 3

Climacteric

Answer 3

• period of transition period

Question 4

Symptoms of menopause

Answer 4

• hot flushes (head, neck, upper chest)
• urogenital atrophy & dyspareunia
• sleep disturbance
• loss of libido
• joint pain

-> symptoms usually diminish/disappear with time

Question 5

Dyspareunia

Answer 5

painful sex

Question 6

What is the normal HPG axis?

Answer 6

• 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

Question 7

How is the HPG axis different in menopause?

Answer 7

Loss of ovarian follicular activity (depletion?) leads to:

• no oestradiol and inhibin production -> low oestradiol
• no negative feedback -> high LH and FSH

Question 8

What are some complications of menopause?

Answer 8

• osteoporosis (oestrogen deficiency, loss of bine matrix, 10x increased risk of fracture)
• Cardiovascular disease (protected before menopause, same risk as men at age 70)

Question 9

What is an important effect of HRT?

Answer 9

• controls vasomotor symptoms (hot flushes)

Question 10

What are the effects of oestrogen in HRT?

Answer 10

• causes proliferation of the endometrium

- risk of endometrial carcinoma

Question 11

What are the effects of progestogens in HRT?

Answer 11

• protect from increased risk of endometrial cancer

Question 12

Which women would oestrogen-only HRT be recommended for?

Answer 12

• women post hysterectomy (basically no risk of endometrial cancer)

Question 13

Why is E+P HRT generally prescribed?

Answer 13

• to prevent endometrial hyperplasia

Question 14

What are the two main HRT formulations?

Answer 14

• Cyclical: E (every day) + P (12-14 days) (add P for 12-14d)
• Continuous combined

Question 15

What are the different ways of administering oestrogen preparations?

Answer 15

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

Question 16

Oestrogens - pharmacology

Answer 16

• very well absorbed
• low bioavailability due to 1. pass metabolism
• groups can be added e.g. ethinyl estradiol or estrone sulphate

Question 17

Estrone sulfate

Answer 17

“conjugated” oestrogen

Question 18

Ethinyl estradiol

Answer 18

• The ethinyl group protects the molecule from first pass metabolism
• semi-synthetic oestrogen
• found in oral contraceptive pills

Question 19

How can most oestrogen preparations be administered?

Answer 19

• orally

- via transdermal skin patches

Question 20

What are the side effects of HRT?

Answer 20

• Breast cancer
• Coronary heart disease
• Deep Vein thrombosis
• Stroke
• Gallstones

Question 21

Absolute risk of HRT?

Answer 21

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

Question 22

HRT and risk of CHD

Answer 22

• 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

Question 23

Why does O only decrease but E+P increase the risk of CHD?

Answer 23

• synthetic progestins negate the protective effects of oestrogen

Question 24

What are the effects of oestrogen on CHD?

Answer 24

• beneficial effects on lipid profile & endothelial function

Question 25

Why is oestrogen harmful with regards to CHD in women >60 years of age?

Answer 25

- they probably have atherosclerosis | - are susceptible to prothrombotic & proinflammatory effects of oestrogen

Question 26

Tibolone

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

SERM

Answer 27

selective oestrogen receptor modulator e.g. Raloxifene

Question 28

Raloxifene

Answer 28

- 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

Tamoxifen

Answer 29

- anti-oestrogenic in breast tissue | - Used to treat oestrogen-dependent breast tumours & metastatic breast cancers

Question 30

Premature ovarian insufficiency

Answer 30

Menopause occurring before the age of 40

Question 31

What fraction of women are affected by premature ovarian insufficiency?

Answer 31

1%

Question 32

What are the causes of premature ovarian insufficiency?

Answer 32

- chemotherapy - radiation - surgery - autoimmune

Question 33

What is in the combined oral contraceptive pill?

Answer 33

Oestrogen (ethinyl oestradiol) + Progestogen (e.g. levonorgestrel or norethisterone)

Question 34

How does the oral contraceptive pill work?

Answer 34

- Suppress ovulation: - E&P: negative feedback actions at hypothalamus/pituitary - P thickens cervical mucus

Question 35

Administration of COCP

Answer 35

Take for 21 days (or 12 weeks), stop for 7 days

Question 36

When would you give a progesterone only contraceptive pill?

Answer 36

- in smokers - >35 years of age - migraine with aura - people with increased risk of thrombosis?

Question 37

Administration of progesterone only oral contraceptive pill

Answer 37

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

Question 38

Name examples of emergency (post coital) contraception

Answer 38

- copper IUD - levonorgestrel - Ulipristal

Question 39

Copper IUD

Answer 39

- exclude pregnancy first - affects sperm viability and function - Effectiveness not reduced in overweight/obese women - 5 (up to 7) days after unprotected intercourse

Question 40

Levonorgestrel

Answer 40

- efficiency reduces with time so take ASAP after unprotected sex - within 72 hours!!

Question 41

Ulipristal

Answer 41

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