Drugs affecting Reproductive Function Flashcards
Sources of Oestrogens
Synthesised in the ovary, placenta and in small amounts in the adrenal cortex and testes. There are 3 main endogenous oestrogens; oestradiol (most potent and principal oestrogen secreted by ovary), oestrone and oestriol.
Mechanism of Action and Effects of Oestrogens
- Main mechanism of action involves interaction with nuclear receptors (ERalpha and ERbeta) to regulate gene transcription.
- Some oestrogen effects (rapid vascular actions) are initiated by interaction with membrane receptors (e.g. GPER).
- Effects of oestrogen depend on the state of sexual maturity.
- In primary hypogonadism, oestrogens stimulate development of secondary sexual characteristics and accelerate growth.
- In adults with amenorrhoea given cyclically with progestogen, they induce an artificial menstrual cycle.
- Given at or after the menopause, they prevent menopausal symptoms and protect against bone loss but increase coagulability of blood and increase risk of thromboembolism.
Clinical uses of Oestrogens
- Replacement therapy in primary ovarian failure (Turner Syndrome) to promote sexual maturation.
- Replacement therapy for menopausal symptoms such as flushing, vaginal dryness and osteoporosis.
- In contraception, they are used singly or in combination with progestogens.
- Prostate and breast cancer.
- When administered to males they cause feminisation.
Clinical Uses of Anti-Oestrogens/Selective Oestrogen Receptor Modulators (SERMs)
- Competitive antagonists/partial agonists of oestrogen are SERMs
- TAMOXIFEN - drug used in oestrogen-dependent breast cancer (anti-oestrogenic action on mammary tissue)
- RALOXIFENE - drug used to treat post-menopausal osteoporosis (antioestrogenic effects on breast and uterus but oestrogenic action on bone).
- CLOMIPHENE - pure oestrogen antagonist at the hypothalamus and pituitary which acts to block negative feedback which leads to increased gonadotropin secretion, increased E2 and ovulation.
Clinical Uses of Progestogens
- Main use is oral contraceptive pill alone or in combination with oestrogen.
- Used as progesterone only injectable or implantable contraception or part of an intrauterine device.
- Combined with oestrogen for oestrogen replacement therapy in women, with an intact uterus, to prevent: endometrial hyperplasia, carcinoma and endometriosis.
Clinical Uses of Anti-Progestogens
Mifepristone in combination with prostaglandin analogues is an effective medical alternative to surgical termination of early pregnancy (up to nine weeks)
What are the changes which occur after menopause?
- Headaches and hot flashes
- Teeth loosen and gums recede
- Hair becomes thinner and loses luster
- Breasts droop and flatten
- Nipples become smaller and flatten
- Risk of cardiovascular disease
- Backaches
- Skin and mucous membranes become drier, skin develops a rougher texture.
- Abdomen loses some muscle tone
- Body and pubic hair becomes thicker and darker
- Stress or urge incontinence
- Bones lose mass and become more fragile
- Vaginal dryness, itching and shrinking
Examples of Synthetic Oestrogens
- Mestranol
- Ethinylestradiol
- Diethylstilbestrol
Many preparations exist (oral, transdermal, intramuscular, implantable, topical) and well absorbed from the gut, across the skin and mucous membranes. In blood they bind to albumin and to a sex hormone-binding globulin (active when unbound). Unwanted side-effects include - breast tenderness, nausea, vomiting and increased risk of thromboembolism.
Examples of SERMs
- Tamoxifen
- Raloxifene
- Clomiphene
Examples of Progestogens
- Derivatives of natural progesterone - medroxyprogesterone & hydroxyprogesterone
- Testosterone derivatives - norethisterone & ethynodiol
- Newer Progestogens - desogestrel & gestodene
Example of Anti-Progestogens
Mifepristone
Combined Contraceptive Pill
- Extremely effective
- The oestrogen in most combined pills ethinyloestradiol or mestranol. Oestrogen content is generally 20-50micrograms (advice is to use lowest dose which is well tolerated and gives good cycle control). The progesterone can be norethisterone, levonogestrel, ethynodiol or in 3rd gen pills, desogestrel or gestodene.
- Most combined pills are taken for 21 consecutive days followed by 7 days pill free to allow a withdrawal bleed. Menstrual cycles return quickly after discontinuation.
- Mode of action - oestrogen inhibits secretion of FSH via negative feedback on ant. pituitary and thus suppresses development of ovarian follicle. Progestin inhibits LH secretion and prevents ovulation. They act in concert to alter the endometrium in such a way to discourage implantation. They may also interfere with coordinated contractions of the cervix, uterus, fallopian tubes that facilitate fertilisation and implantation.
- Adverse effects - mild nausea, flushing, dizziness, bloating, weight gain, skin changes e.g. acne or pigmentation, depression or irritability. Amenorrhoea of variable duration after cessation of taking the pill. Serious withdrawal effects are rare. Small number of women develop reversible hypertension and increase risk of thromboembolism.
Progestin Only Contraceptive Pill
- Norethisterone, Levonorgestrel, Ethynodiol Diacetate, Desogestrel
- Taken daily without interruption.
- In addition to reducing LH secretion through negative feedback, it makes cervical mucous inhospitable to sperm. Also hinders implantation through its effect on the endometrium and on the motility and secretions of the uterine tubes.
- Just as reliable as the combined pill.
- Suitable alternative to oestrogen-containing pills when they are contraindicated.
Post-Coital Emergency Contraception
Oral administration of Levonogestrel alone or in combination with oestrogen is effective if taken within 72 hours and repeated 12 hours later.
Long-acting Progestogen Only Contraception
- Levonorgestrel (norplant) subcutaneous implant (5yrs) or Etonogestrel (Nexplanon) subdermal implant (3yrs).
- Medroxyprogesterone acetate can be given intramuscularly as a contraceptive. This is effective and safe.
- A levonorgestrel impregnated intrauterine device can last for 35 years.
