Contraceptives, HRT and SERMS

Question 1

What is menopause?

Answer 1

Permanent cessation of menstruation.

Loss of ovarian follicular activity.

Average age 51 (range 45-55).

Climacteric: period of transition.

Question 2

What are the symptoms of menopause?

Answer 2

Hot flushes (head, neck, upper chest).

Urogenital atrophy and dyspareunia.

Sleep disturbance.

Depression.

Decreased libido.

Joint pain.

Symptoms usually diminish/disappear with time.

Question 3

Describe the normal HPG axis in females.

Answer 3

Pulses of GnRH released from the hypothalamus stimulate LH and FSH release from the anterior pituitary, in turn stimulating oestradiol/inhibin B production from the ovaries, which negatively feedback on the pituitary and hypothalamus.

Question 4

If follicular activity is reduced, e.g. in menopause, what happens to the oestradiol levels?

Answer 4

Reduced.

Question 5

If follicular activity is reduced, e.g. in menopause, what happens to the LH and FSH levels?

Answer 5

Increased due to reduced negative feedback on pituitary and hypothalamus by oestradiol (reduced).

Question 6

What are the possible complications of menopause?

Answer 6

Osteoporosis: oestrogen deficiency, loss of bone matrix, 10-fold increased risk of fracture.

Cardiovascular disease: protected against CVD before menopause, have the same risk as men by the age of 70.

Question 7

What is the purpose of hormone replacement therapy (HRT)?

Answer 7

Control vasomotor symptoms (hot flushes).

Question 8

What are the constituents of hormone replacement therapy (HRT)?

Answer 8

Oestrogen (E): endometrial proliferation, risk of endometrial carcinoma.

Progestogens (P).

E+P to prevent endometrial hyperplasia.

If hysterectomy, E only.

Question 9

What are the different HRT formulations?

Answer 9

Cyclical: oestrogen (every day) and progestogens (12-14 days).

Continuous combined.

Question 10

What are the different oestrogen preparations?

Answer 10

Oral oestradiol (1mg).

Oral conjugated equine oestrogen (0.625mg).

Transdermal (patch) oestradiol (50 micrograms/day).

Intravaginal- local effect on dyspareunia.

Question 11

Discuss the pharmacokinetics of the different oestrogens.

Answer 11

Oestradiol (oral) is well absorbed but has low bioavailability (first pass metabolism).

Oestrone sulphate (‘conjugated’ oestrogen).

Ethinyl oestradiol: a semi-synthetic oestrogen- the ethinyl group protects the molecule from first pass metabolism.

Most oestrogen can also be administered via transdermal skin patches.

Question 12

Wha are the possible side effects of HRT?

Answer 12

Breast cancer.

Coronary heart disease.

Deep vein thrombosis.

Stroke.

Gallstones.

The absolute risk of complications for healthy symptomatic postmenopausal women in their 50s taking HRT for 5 years is very low.

Question 13

Why were the Women’s Health Initiative (WHI) trials that showed an increased risk of CHD events in women on HRT insufficient in their evidence?

Answer 13

Mean age: 63 years.

Timing of exposure important.

No excess risk in younger menopausal women.

Women < 10 years since menopause or 50-59 years: no excess risk.

Question 14

How many additional cases of invasive breast cancer are seen per 1000 women taking combined (E+P) HRT for 5 years?

Answer 14

3.

Question 15

How many additional cases of CHD are seen per 1000 women taking combined (E+P) HRT for 5 years?

Answer 15

2.5.

Question 16

How many additional cases of DVT are seen per 1000 women taking combined (E+P) HRT for 5 years?

Answer 16

5.

Question 17

How many additional cases of stroke are seen per 1000 women taking combined (E+P) HRT for 5 years?

Answer 17

2.5.

Question 18

What are the effects of oestrogen and progesterone as HRT treatment in women aged 50-59?

Answer 18

Oestrogen alone has beneficial effects on lipid profile and endothelial function.

Synthetic progestins negate these effects of oestrogen.

Question 19

What are the effects of oestrogen and progesterone as HRT treatment in women over the age of 60?

Answer 19

Atherosclerosis.

Susceptible to pro-thrombotic and pro-inflammatory effects of oestrogen.

Increased risk of CHD.

Question 20

What is tibolone?

Answer 20

Synthetic pro-hormone.

Oestrogenic, progestogenic and weak androgenic actions.

Reduces fracture risk.

Increased risk of stroke (RR: 2.2).

? increased risk of breast cancer.

Question 21

What is raloxifine?

Answer 21

Selective oestrogen receptor modulator (SERM).

Oestrogen in bone: reduces risk of vertebral fractures.

Anti-oestrogenic in breast and uterus: reduces breast cancer risk.

Does not reduce vasomotor symptoms.

Increased risk of VTE (venous thromboembolism) and fatal stroke.

Question 22

What is tamoxifen?

Answer 22

Anti-oestrogenic on breast tissue.

Used to treat oestrogen-dependent breast tumours and metastatic breast cancers.

Question 23

What is premature ovarian insufficiency?

Answer 23

Menopause occurring before the age of 40.

1% of women.

May be caused by autoimmunity, surgery, chemotherapy, radiation.

Question 24

What are the constituents of combined oral contraceptives?

Answer 24

Oestrogen (ethinyl oestradiol) and progestogen (e.g. levonorgestrel or norethisterone).

Question 25

What is the action of combined oral contraceptives?

Answer 25

Suppress ovulation.

E&P: negative feedback actions at hypothalamus/pituitary on LH and FSH secretion, therefore less ovulation.

P thickens cervical mucus.

Question 26

When are progesterone only contraceptives used?

Answer 26

When oestrogens are contraindicated, e.g. smokers, >35 years old, migraine with aura.

Question 27

Why must progesterone only contraceptives be taken at the same time each day?

Answer 27

Short half-life.

Short duration of action.

Question 28

What are the different types of emergency (post-coital) contraception?

Answer 28

Copper IUD (intrauterine contraceptive device): exclude pregnancy first, affects sperm viability and function.

Levonorgestrel (within 72 hours).

Ulipristal (up to 120 hours after intercourse): anti-progestin activity, delays ovulation by as much as 5 days, impairs implantation.