Oestrogens & Progestogens

• Naturally occurring oestrogens include oestradiol, oestriol and oestrone
• Oestrogens used therapeutically include ethinyloestradiol, mestranol and conjugated oestrogens
• The main naturally occurring progestogen is progesterone
• Progestogens used therapeutically include:

1. Derivatives of progesterone (such as medroxyprogesterone acetate),
2. Derivatives of testosterone (such as norethisterone, norgestrel and its active isomer levonorgestrel)
3. Newer, third generation progestogens (gestodene, desogestrel and norgestimate – all derivatives of norgestrel)
4. The most recent progestogen (drospirenone) is a derivative of spironolactone

Clinical use of oestrogens & progestogens
Contraception

• In combined oral contraceptive pills
• In progesterone-only contraceptives

Treatment of menstrual disorders

• Progestogens used for treatment of heavy periods (dysfunctional uterine bleeding) and to induce amenorrhoea in women with painful periods (dysmenorrhoea)

Hormone replacement therapy

• Oestrogens used on their own (in women with a hysterectomy) or in combination with progestogens (in women who still have their uterus) for hormone replacement therapy to treat menopausal symptoms.

COMBINED ORAL CONTRACEPTIVE PILL

• Contain ethinyloestradiol (20-50mcg) or mestranol (a prodrug which is converted to ethinyloestradiol) and a progestogen
• Progestogen is second generation (Norethisterone or levonorgestrel), third generation (gestodene, desogestrel or norgestimate) or spironolactone derivative drospirenone
• Mode of action
• Suppress ovulation
• Disrupt endometrium preventing implantation
• Thicken cervical mucus reducing sperm penetration

Side-effects

• Nausea and vomiting
• weight change
• Headache
• Deep vein thrombosis
• Chloasma (darkening of the skin, especially on the face)
• Hypertension
• Impaired liver function
• Unscheduled vaginal bleeding

PROGESTOGENS

NORETHISTERONE

• 19-Nortestosterone derivative
• Second generation progestogen
• The prodrug ethynodiol is converted to norethisterone in vivo
• Has androgenic effects

MEDROXYPROGESTERONE ACETATE

• Derivative of progesterone
• Less androgenic effects compared to norethisterone

Clinical use of progestogens

• Contraception – combined oral contraceptives / progestogen-only contraceptives
• Menstrual disorders – menorrhagia, dysmenorrhoea and metrorrhagia
• Treatment of endometriosis
• Hormone replacement therapy

Side-effects of progestogens

• Androgenic side-effects – acne, oily skin, increased facial hair: worse with norethisterone compared to medroxyprogesterone acetate
• Fluid retention / weight gain
• Breast discomfort
• Irregular vaginal bleeding
• Low mood / depression

TIBOLONE

• Synthetic agent with oestrogenic, progestogenic and weak androgenic activity
• Used in prophylaxis for postmenopausal osteoporosis and in the treatment of menopausal symptoms and as add-back during GnRH therapy
• Given orally and continuously without cyclical progesterone

ANTI-OESTROGENS

• Anti-oestrogen drugs have varying effects on different organs / tissues. In addition to anti-oestrogenic effects, the majority also have oestrogenic effects on some tissues.

CLOMIPHENE CITRATE

Clinical use

• Ovulation induction in women with sub-fertility secondary to anovulation (typically polycystic ovary syndrome).

Action

• Antagonises negative feedback effects of oestrogen on the pituitary gland and hypothalamus, resulting in increased GnRH, FSH and LH levels which stimulate the ovaries and induce ovulation  
• Non-steroidal anti-oestrogen with weak oestrogenic effects
• Active orally, has long half life and significant plasma concentrations can be detected 1 month after a single 50mg dose
• Administered from days 2-6 of the cycle
• Use should be limited to a 6 months course

Contraindications

• Hepatic disease, ovarian cysts and hormone dependent tumours

Side-effects

• Visual disturbance, hot flushes, ovarian hyperstimulation, multiple pregnancy, hair loss, breast tenderness, headache

TAMOXIFEN

Clinical use

• Secondary prevention of breast cancer, making use of its anti-oestrogenic effects on the breast. May also be used for induction of ovulation in women with sub-fertility secondary to anovulation

Action

• Blocks oestrogen receptors in the breast
• Has  anti-oestrogenic effects on the pre-menopausal uterus
• However, has oestrogenic effects on the post-menopausal uterus, increasing the  risk of endometrial hyperplasia and carcinoma

Side-effects

• Hot flushes (anti-oestrogenic effect), visual disturbance, amenorrhoea, irregular vaginal bleeding, GI disturbance, hair loss, thromboembolism

RALOXIFEN

• This is the archetypal Selective oEstrogen Receptor Modulator (SERM) developed to maximise the anti-oestrogenic effects on specific tissues without the potentially damaging oestrogenic effects on other tissues

Clinical use

• Used in the treatment and prevention of post-menopausal osteoporosis
• Oestrogen-antagonist in breast therefore not associated with increased risk of breast cancer
• Oestrogen antagonist / neutral on the uterus – therefore not associated with increased risk of endometrial cancer (unlike tamoxifen).
• Does not relieve hot flushes

Side-effects

• Hot flushes, leg cramps, thromboembolism, GI upset and flu-like symptoms

ANTI-PROGESTOGENS

Mifepristone (RU486)

• Derivative of norethindrone (19-norsteroid) - similar chemical structure to progesterone / glucocorticoids
• Progesterone / glucocorticoid antagonist
• Administered orally
• Acts on the high concentration of progesterone receptors in decidua resulting in withdrawal of progesterone support, disruption of placental function and uterine bleeding
• Detachment of chorionic tissue results in a fall in HCG levels, degeneration of the corpus luteum and further withdrawal of hormonal support to the endometrium

Clinical use

• Termination of pregnancy - on its own, mifepristone results in complete medical abortion in 60-80% of subjects - this is improved by the administration of prostaglandins 36-48h later
• Pre-treatment with mifepristone reduces the interval between prostaglandin administration and expulsion
• Mifepristone increases uterine concentration of prostaglandins (probably by inhibiting prostaglandin metabolism) and also increases the sensitivity of the myometrium to prostaglandins
• Licensed for use in early medical termination of pregnancy up to 63 days from last menstrual period with administration of prostaglandins (oral / vaginal) 36-48h after mifepristone
• Success rate 94 - 96% with continuation of pregnancy in ~0.3%
• Also licensed for use in second trimester (13-20 weeks) termination of pregnancy

SIDE-EFFECTS

• Vaginal bleeding, Malaise, Headache, Nausea, Vomiting, Rash

CONTRA-INDICATIONS

• Suspected ectopic pregnancy
• Chronic adrenel insufficiency
• Long-term corticosteroid therapy
• Haemorrhagic disorders
• Anti-coagulant therapy
• Smokers over the age of 35 (avoid smoking / alcohol 2 days before and on the day of prostaglandin administration)
• Hepatic / renal impairment
• Avoid aspirin / NSAIDS for at least 8-12 days after mifepristone.