Hormones of pregnancy, menopause & contraception

Question 1

Sex hormones act through nuclear receptors

Answer 1

Common properties:
Have ligand-binding (hormone-binding) and DNA-binding domains
Translocate to nucleus once hormone bound
Bind to hormone-response elements (recognition elements) in specific gene sequences
Dimerization important for function
Androgen receptors (AR), Estrogen receptors (ER), Progesterone receptors (PR)

Question 2

Oestrogen receptors

Answer 2

The receptor changes conformation due to the dissociation of heat shock proteins after oestrogen binds

The receptor undergoes dimerization in order for increased affinity to DNA

This oestrogen-receptor complex can now bind to specific DNA sites, called oestrogen response/ recognition elements (EREs).

Question 3

Progesterone receptors

Answer 3

Nuclear receptors regulating gene transcription – like ER

There is a single gene that encodes the progesterone receptor – PR; bind to PREs

Two isoforms – PR-A and PR-B
Identical ligand binding
PR-B mediates the stimulatory effects of progesterone

Question 4

Actions of oestrogens

Answer 4

Metabolism
Protein anabolism
Bone growth
↓ Circulating cholesterol

Pituitary
↓ LH secretion

CNS
Multiple effects

Female sexual characteristics
Secondary sex characteristics
Development breast ductal system

Ovaries/ Uterus
Stimulation of endometrium
Thickening of vaginal mucosa
Thinning of cervical mucus

Hypothalamus
↑GnRH secretion

Question 5

Actions of progesterone

Answer 5

Produced in luteal phase, decreases GnRH production

Induction of secretory activity in oestrogen-primed endometrium

increase Viscosity cervical mucous

Promotes glandular breast development

increase Basal body temperature

Question 6

Oestrogen preparations

Answer 6

Natural oestrogens
Oestradiol/ Oestrone
Oestriol

Synthetic oestrogens
Mestranol
Ethinylestradiol
Diethylstilbestrol

Availability: oral, transdermal, intramuscular, implantable, topical

Question 7

SERMs (Selective Estrogen Receptor Modulators)

Answer 7

Selectivity is possible because

ER- and/or ER- show differential tissue expression

Conformation dependent binding to DNA and transcription factors

Tissue dependent responses ranging between pro-oestrogenic, partially oestrogenic and anti-oestrogenic effects

Role in treatment of certain cancers e.g. tamoxifen in breast cancer

Question 8

Progestogen preparations

Answer 8

Natural progestogens
hydroxyprogesterone
medroxyprogesterone
dydrogesterone

Testosterone derivatives
norgestrel
desogestrel
ethynodiol

Availability: oral, intramuscular, via vagina/rectum

Question 9

Menopause

Answer 9

Menopause normally occurs 45-55 yrs
Menstruation becomes irregular & then ceases
Caused by “ovarian failure”
Gonadotropins secreted in greater amounts, because of loss of negative feedback

Question 10

Phases of Menopause

Answer 10

Perimenopause
Fluctuation in hormone levels
Can last 2-8 years
Menopause
Oestrogen levels drop
1 year after cessation of menstrual cycle
Postmenopause
Oestrogen levels continue to drop

Menopause associated with change in risk for cardiovascular disease, stroke, osteoporosis, dementia

Question 11

Symptoms of menopause

Answer 11

About 80% of women can experience post-menopausal symptoms mainly associated with  in oestrogen levels
Hot flushes of skin
Night sweats
Palpitations
Low mood/anxiety
Impaired memory/brain fog
Recurrent headaches/ migraines
Vaginal atrophy
Development of osteoporosis (  risk hip & spine fractures)

Question 12

Osteoporosis

Answer 12

Oestrogen acts to maintain bone mineral density
There is a positive relation between maintenance of bone mass and HRT with oestrogen
Decrease rates of wrist, non-vertebral, vertebral, and hip fractures
Raloxifene – SERM that functions like oestrogen to maintain bone density

Question 13

Hormone Replacement Therapy (HRT)

Answer 13

Generally use “natural” oestrogen rather than more potent synthetic derivatives
Oestrogens + progestogens in women with an intact uterus
Combination preparations (tablet, patch) (cyclical)
Oestrogen only preparation (transdermal patch, gel, spray) PLUS progesterone (tablet, intrauterine device)

Question 14

HRT – Effects of Treatment

Answer 14

Oestrogen associated with good and bad effects during menopause

HRT can reduce post-menopausal osteoporosis & vasomotor symptoms
Oestrogens lower LDL cholesterol levels but evidence mixed about lower risk of coronary heart disease
For most women the benefits of HRT outweigh the risk of breast cancer, blood clots, cardiovascular disease

Question 15

HRT – Effects of Treatment- good effects

Answer 15

strengths bones
lowers LDL
increases HDL
reduces menopausal symptoms .eg hot flush

Question 16

HRT – Effects of Treatment- bad effects

Answer 16

increases the risk of breast cancer
increases the risk of uterine cancer
increases blood clot risk

Question 17

Contraception

Answer 17

Barrier methods
Caps, diaphragms, condoms

Intra-uterine devices (IUD) “coil”

Oral contraceptives
Combined hormonal contraceptives
Progestogen-only contaceptives
Emergency contraception

Question 18

Combined oestrogen/progestogen preparation for oral contraception (COCs)

Answer 18

Ethinylestradiol or mestranol PLUS levonorgestrel/ desogestrel/ gestodene

Taken 21/28 days

Oestrogen – inhibits secretion of FSH via negative feedback on the pituitary

Progestogens – inhibit LH secretion and induces thickening of cervical mucus & thins endometrium

Question 19

Side effects with COCs

Answer 19

Mild side effects are mostly related to the oestrogen content
Nausea, vomiting
Weight gain (Na+/ fluid retention)
Mild hypertension
Breast tenderness

More serious (and rare) side effects:
Venous thromboembolism (oestrogen increase coagulation)
Cerebral haemorrhage/ embolism/stroke, myocardial infarction (especially in heavy smokers & 35+)
Increased risk of breast/cervical cancer
Amenorrhoea following withdrawal can last several months

Question 20

Progestogen-only contraceptive (POC)

Answer 20

Norethisterone, levonorgestrel, ethynodiol

Taken continuously, effects include:

Cervical mucus becomes thick & sticky
Endometrium changes so implantation less likely
Weak negative feedback inhibition of LH release & ovulation
POC’s in some women can completely suppress gonadotrophin secretion & ovulation resulting in amenorrhoea.

Question 21

Menstrual Disorders

Answer 21

Progestogens are also used in
Dysmenorrhoea
Painful periods, abdominal cramps

Menorrhagia
Heavy periods, excessive blood loss

Premenstrual syndrome
Physical, psychological, behavioural symptoms

Endometriosis
Long-term condition

Question 22

“Emergency contraception”Postcoital oral contraception

Answer 22

Pregnancy can be prevented by short-term administration of a high dose of progestogen - the “morning after pill”, “plan-B”

Used within 72 h of unprotected intercourse it is 98% effective

Ulipristal is a PR modulator - effective within 5 days

Side effects: nausea, vomiting (can affect absorption), cardiovascular and metabolic effects, breast tenderness

Question 23

Antiprogestogens

Answer 23

Mifepristone – PR antagonist
Used in combination with a prostaglandin - gameprost
“Medical abortion” - an alternative to surgical termination of pregnancy