8. Sex steroids Flashcards
What are sex steroid hormones synthesised from?
Cholesterol
What receptors do steroid hormones have?
- Classic nuclear receptors
- Exert effects through gene transcription
- But also a membrane receptor for oestrogen
what are the 3 main sex steroid hormones?
Oestrogens, progestagens, androgens
What are the major effects of oestradiol?
Stimulates growth of the endometrium and breast; stimulates production of Progesterone receptor (PR).
What are the major effects of progesterone?
Stimulates growth of the endometrium and breast; maintains pregnancy; inhibits production of ER(oestrogen receptor).
What are the major effects of testosterone?
Stimulates male characteristics; hairy body; deep voice; anabolism; aggression.
What are the actions of oestrogen?
- Mild anabolic
- Sodium and water retention
- Raises HDL, lowers LDL
- Decrease bone resorption (oestrogen decreases osteoclast function)
- Impair glucose tolerance
- Increase blood coagulability
What are the side effects of oestrogen?
- Breast tenderness
- Nausea, vomiting
- Waterretention
- Increased blood coagulability
- Thromboembolism
- Impaired glucose tolerance
- Endometrial hyperplasia & cancer
- Ovarian metaplasia & cancer
- Breast hyperplasia & cancer
What are the actions of progesterone?
- Secretory endometrium
- Anabolic
- Increases bone mineral density
- Fluid retention
- Mood changes
- Maintains pregnancy
What are the side effects of progesterone?
- Weight gain
- Fluid retention
- Anabolic
- Acne
- Nausea/vomiting
- Irritability Depression, PMS
- Lack of concentration
What are the actions of testosterone?
- Male secondary sex characteristics
- Anabolic
- Voice changes
What are the side effects of testosterone?
Metabolic - adverse effects on lipid profiles particularly the HDLC/LDL-C ratio hence increased risk of atherosclerotic disease in males
• Acne
• Increases aggression
describe the role of oestrogen and progesterone in the menstrual cycle
- Ovulation occurs due to the LH surge
- Oestrogen and progesterone have differing effects on endometrial tissue and on cervical mucus
- oestrogen promotes thin watery mucus for stern transport and progesterone promotes thick cervical mucus to block any further sperm from entering
- Oestrogen and progesterone together produces suppression of the HPO axis
What are the pharmacokinetics of oestrogen?
- Natural and synthetic oestrogens well absorbed in the GI tract
- Also readily absorbed from skin and mucous membranes
- Metabolism - liver
- Excretion - in the urine as glucuronides and sulfates
What are the pharmacokinetics of progesterone?
- Injected progesterone is bound to albumin with some stored in adipose tissue
- Metabolised in the liver
- Metabolites excreted in the urine conjugated to glucuronic acid
WHat are COCP and POP metabolised by?
CYP enzymes
what are Adverse effects of the combined pill?
• small Risk of thromboembolism
what increases the risk of thromboembolism with COCP?
- Smoking increases this risk substantially
- Also for long-term use in women over 35
- Also consider other risk factors such as obesity and hypertension
Give examples of drugs that reduce efficacy of oral contraceptives and how?
- anti-epileptics such as carbamazepine or phenytoin;
- some antibiotics such as rifampicin and rifabutin and
- some natural products such St John’s Wort
All increase production of hepatic CYP450 so speed up metabolism of drug
What increases absorption of oestrogen?
Soya protiens - also reduce oestrogen storage in adipose tissue and decrease its half life
What is HRT prescribed for?
- symptoms of menopause: e.g. hotflushes /sweats and vaginal dryness / dyspareunia
- osteoporosis - both oestrogen and progesterone limit bone resorption
(should not be given for heart disease)
what is menopause and what causes symptoms?
• Ovarian follicle supply depleted
• Consequently ovarian sex steroid production stops
• End of female reproductive capacity
• ALSO
Loss of oestrogen and progesterone leads to a range of systemic effects as symptoms of menopause
which steroids are used for HRT?
• Oestradiol: e.g. valerate, enanthate, micronised oestradiol, ethinyl estradiol, etc.
(1-2 mg/day)
• Premarin® (0.625-1.25 mg/day)
• Medroxyprogesterone acetate (Provera®) (2.5 mg/day) • Norethisterone (1 mg/day)
• Levonorgestrel (1.5 mg/day)
what are the routes of administration of HRT?
ORAL TRANSDERMAL IMPLANT TRANSVAGINAL NASAL
WHat are the risks of HRT?
▪ Unopposed oestrogen (ERT): increases risk of developing endometrial and ovarian cancers
▪ Opposed oestrogen (HRT): increases risk of developing breast cancer
▪ Increase risk of venous thromboembolism
▪ Cardiovascular disease
▪ Increased risk of stroke
What are the effects of HRT on thromboembolism profile?
- Increased activated protein C resistance
- increased thrombin activation,
- decreased anti-thrombin III activity,
- decreased protein S levels,
- decreased Factor VII levels and
- decreased tissue factor pathway inhibitor (but only for oral delivery systems)
What are the effects of HRT on lipid profile?
Beneficial effect on lipid profile
- increased HDL-C,
- decreased oxoLDL-C,
- decreased triglyceride,
- decreased lipoprotein(a)
what drugs are used to treat osteoporosis?
Bisphosphonates
what is the action of bisphosphates?
- Class of drugs that reduce bone turnover
* Act by controlling osteoclast activity
what are bisphosphates used for?
- Prophylaxis and treatment of osteoporosis
- Other uses include management of other diseases involving bone
- e.g. Paget’s disease of bone, malignancy
What are the pharmacokinetics of bisphosphates?
- Long biological half life
- Poor gut absorption
- Absorption affected by food
- Therefore must be taken on an empty stomach
what re the ADRs of bisphosphates?
• Upper GI effects
- Oesophagitis
- Stress the importance of remaining seated or standing for 30 minutes after taking
• Hypocalcaemia
- Check calcium and Vit D levels prior to initiating treatment
what is an example of a bisphosphate?
alendrotnic acid
What is Mifepristone (RU486)?
Progesterone (and glucocorticoid) receptor antagonist
What is Mifepristone (RU486) used for?
Sensitising the myometrium to prostaglandin-induced contractions
- Used for termination of pregnancy
- progestogen usually cause inactivity of myometrium and prevents contractions
What are SERMs?
• Selective Estrogen Receptor Modulator
• SERMs are distinct in having varying effects in differing tissues
i.e. are not pure agonists/antagonists
What are 3 SERMs?
• Tamoxifen • Raloxifene • Clomiphene
what can raloxifene be used for?
treatment of osteoporosis - has oestrogen effects on bone without harmful effects of breast and endometriun
What is clomiphene used for?
- Clomiphene used in the treatment of anovulation
what is the action of clomiphene?
- Competes with oestrogen for ER binding (in anterior pituitary, preventing negative feedback)
- Leads to ovulation induction through increased production of anterior pituitary hormones
Where is tamoxifen metabolized?
Liver - it is a prodrug, it has little affinity for ER
What is tamoxifen used for?
To treat and prevent recurrence of ER-positive breast cancer
- ER antagonist in the breast, puts cells in cell cycle arrest
describe the converse effects of tamoxifen in breast tissue and endometrium
- In endometrium, acts as ER agonist
* In breast, acts as ER antagonist
What is the risk of using tamoxifen?
It is an ER agonist in the endometrium, risk of endometrial cancer
Give an example of a selective progesterone receptor modulator?
Ulipristal acetate
What is ulipristal acetate used for?
- used for emergency contraception (morning after pill)
- (effective for the treatment of uterine fibroids)
How does ulipristal acetate work?
primary mode of action is thought most likely to be delay or inhibition of ovulation
- suppression of LH surge?
