Oral contraceptives, menopause and HRT

Question 1

What are the different types of oestrogen contraceptive/HRT?

Answer 1

Oestrone sulphate (‘conjugated’ oestrogen)

Oestriol

Ethinyl oestradiol – the ethinyl group protects the molecule from first-pass metabolism

Question 2

What pharmacokinetic considerations need to be taken into account when administering exogenous oestrogen and progesterone?

Answer 2

Oestradiol is well absorbed but has a LOW bioavailability (extensive first-pass metabolism)

• A lack of oestrogen leads to an increased chance of osteoporosis and fracture.
• *Oestrogen also contributes to breast growth (cancer) and CVS problems (VTE, stroke)

Progesterone is poorly absorbed and rapidly metabolised in the liver.

Can be given as an IM injection or depot preparation.

Many oral therapies are available – e.g. norethisterone.

Question 3

What is Combined Oral Contraceptive?

Answer 3

This is a combination of an oestrogen (ethinyl oestradiol) and a progestogen (levonorgestrel or norethisterone).

This synthetic combination supresses ovulation via multiple mechanisms:
- Feedback of oestrogen and progestogens on the hypothalamus and pituitary.

• Progestogens thicken cervical mucus.
• Oestrogen upregulates progestogen receptors.
• Oestrogen counteracts the androgenic effects of synthetic progestogens.

The COC is taken for 21 days (or 12 weeks) and is then stopped for 7 days

Question 4

What are theunwanted side effects of oestogen?

Answer 4

• nausea
• headache
• increased weight - water retention and fat deposition
• CVS problems - increased risk of fatal stroke and VTE

breast - oestrogen dependent cancers

• endometrium - causes proliferative effects

Question 5

When are progesterone-only contraceptives used?

How are the administered?

Answer 5

These are used when oestrogens are not a good idea – i.e. CVS problems, history of thrombosis.

Administration:

• Long-acting preparations may be given by deep IM injection or via intra-uterine system.
• Oral (POP – progesterone only pill

Question 6

What are the emergency contraceptives?

Answer 6

post-coital pill

Levonorgestrel – combined E+P or P-only - 2 doses 12 hours apart beginning ASAP within 72 hours of intercourse.

• A single one-dose double strength also available.
• May cause nausea and vomiting.

Copper IUD.

Ulipristal – up to 120 hours after intercourse.
- Delays ovulation up to 5 days with anti-progestin activity.

Question 7

What is menopause?

Answer 7

permanent cessation of menstruation resulting from the loss of ovarian follicular activity.

• Average age: 51 (45-55)

Question 8

What is climacteric?

Answer 8

the period of transition from predictable ovarian function through the postmenopausal years

Question 9

What is premature ovarian failure/insufficiency?

Answer 9

menopause occurring before the age of 40 and occurs in 1% of women.

POF may be autoimmune or secondary to surgery, chemotherapy or radiation

Question 10

Compare the levels of GnRH, LH/FSH and oestrodiol in normal and menopausal women.

Answer 10

hypothalmus GnRH - high in both

pituitary LH/FSH - high in both

ovarian oestrodiol - high in normal, low in menopausal

Question 11

What are the symptoms of menopause?

Answer 11

Hot flushes

Sleep disturbance

Depression

Urogenital atrophy

Decreased libido

Joint pain (lack of oestradiol)

Question 12

What are the complications associated with menopause?

Answer 12

Osteoporosis:

• Oestrogen deficiency leads to loss of bone matrix.
• Loss of 1-3% of bone mass/year and have 10x increase risk of fracture.

Cardiovascular disease:
- Women are protected from CVS disease before the menopause but have the same risk as men by the age of 70

Question 13

How can HRT be used to treat menopause?

Answer 13

oestrogen + progesterone – to prevent endometrial hyperplasia – this reduces risk of cancer

Can be given oral, transdermal, transvaginal:

• Oral oestradiol (1mg) – larger dose orally as undergoes first-pass metabolism.
• Oral conjugated equine oestrogen (0.625mg).
• Transdermal oestradiol (50micrograms/day).
• Intravaginal.

Can be given cyclical (oestrogen every day and progesterone on 12-14 days in) OR continuously.

Does increase risk of breast cancer, VTE, stroke and gallstones but absolute risk for postmenopausal >50s women is very low.

• absolute risk is very low but it may DOUBLE the relative risk
• • HRT to OLDER women has a much more increased risk (better in younger postmenopausal)

E.G. Tibolone – a synthetic prohormone.

• Has oestrogenic, progestogenic and weak androgenic actions.
• Does increase risk of stroke, and possible increase in risk of breast cancer.

HRT – oestrogen-only – only for women that have had hysterectomies (as no endometrium!)

Question 14

How can raloxifene be used to treat menopause symptoms?

Answer 14

selective oestrogen receptor modulator

• Tissue-selective – oestrogenic in bone and anti-oestrogenic in breast and uterus.
• Used in the treatment & prevention of postmenopausal osteoporosis.
• Reduces risk of; vertebral fractures and breast cancer.
• Increases risk of; fatal stroke, VTE.
• Does NOT affect vasomotor symptoms (hot flushes)

Question 15

How is tamoxifen used to treat menopause symptoms?

Answer 15

anti cancer drug

selective oestrogen receptor modulator

• anti-oestrogen in breast tissue
• used to treat oestrogen dependent breast tumours and metastitic breast cancers