Oestrogens, Progestogens, and Contraception Flashcards
What happens in the HPO axis?
The hypothalamo-Pituitary-Ovarian axis starts with the hypothalamus releasing GnRH in a pulsatile and cyclical manner leading to FSH and LH which control different parts of the ovarian cycle. FSH stimulates follicles and production of oestrogens and LH stimulates CL and production of progesterone.
Progesterone and Estrogens are both important negative feedback messengers for this axis.
What are the 3 most important naturally occuring oestrogens?
17beta Estradiol (Most abundant and potent oestrogen produced by ovarian granulosa cells)
Estrone (Produced by ovaries and adrenals)
Estriol (Placental - only in pregnancy)
What features do all endogenous oestrogens share?
They are all 18-carbon steroids
Transported by SHBG
Bind oestrogen receptors (ERalpha and ERbeta) in target cells
Where are oestrogen receptors expressed?
Redundantly in reproductive system and the breast
Also expressed non-redundantly in CVS, skeleton, CNS, and immune system -> non-reproductive effects of oral contraceptives.
What do oestrogen receptors do?
They are ligand activated transcription factors (Target genes with EREs) and have a slow response time.
Important note about ERalpha:
ERalpha is over expressed in approximately 70% of all breast cancers.
Anti-oestrogens that block ERalpha are widely used in breast cancer.
What do oestrogens do?
Important for development of breasts and genitals during puberty.
Menstrual cycle regulation: Modulation of FSH and LH release, cyclical changes in uterus and breasts, and induction of progesterone receptors
Metabolic actions: Increase bone mass by blocking bone resorption. Improved triglyceride profile increasing the HDL:LDL ratio. They increase risk of coagulability which means higher stroke and VTE risk.
What is progesterone’s biochemical properties?
It is a 21 carbon steroid.
It is transported in the blood by binding to albumin and corticosteroid binding globulin.
When is progesterone produced?
After the CL is formed
Secreted in the second half of the menstrual cycle (In the luteal phase)
What does progesterone receptor do?
Ligand activated transcription factor expressed in female reproductive tract, breast, and CNS.
What does progesterone do?
Prepares for and maintains pregnancy.
Uterine / Cervical effects: Endometrium decreases proliferation and initiates secretory changes. Cervix thickens and decreases secretions and sperm penetration. Reduces contractibility of the myometrium.
Initiates glandular development in breasts.
In the hypothalamus it stops the LH surge and GnRH release which allows it to block ovulation.
In the CNS it increases body temperature by ~0.5 degrees
It binds androgen receptor weakly which means it has low pro/anti-androgenic effects.
What are the 2 major groups of oral contraceptives?
Combined contraceptives containing both oestrogen and a progestogen.
Progestogen-only contraceptives.
What are the types of synthetic oestrogens used?
Ethinyloestradiol or Mestranol
What are the progestogens in use?
Levonorgestrel
Norethisterone
Desogestrel
Gestodene
Cyproterone acetate
How have newer Combined Oral Contraceptives changed?
They use much less oestrogen and progestogen.
Why is ethinylestradiol used more often than mestranol?
Ethinylestradiol has an addition of ethinyl which reduces hepatic metabolism making it very potent orally. Mestranol has 50 - 70% of ethinylestradiol’s potency.
How have synthetic progestogens changed over time?
1st generation (ethisterone) had significant androgenic effects like acne, hirsutism and weight gain.
2nd generation had reduced androgenic effects
3rd generation had reduced androgenic and lipid effects. However, there was increased thromboembolic effects.
How do combined oral contraceptives work?
They inhibit ovulation which prevents release of FSH and LH production.
They thicken cervical mucous which forms barrier to sperm
Thin endometrial lining reducing endometrial receptivity to inhibit implantation.
How effective are COCs?
When taken correctly >99%.
How is effectiveness of COC reduced?
Poor compliance (Delayed start of next pack, missed pills, etc)
Vomiting or severe diarrhoea can decrease intestinal absorption.
Broad spectrum antibiotics decrease enterohepatic circulation
CYP3A4 induction (griseofulvin, anti-epileptics, TB drugs (rifampicin), and St John’s Wort)
How are COC pills taken?
Available in 2 regimens:
21 days OC + 7 days no pill
21 days OC + 7 days placebo
What happens if COC is withdrawn?
7 days hormone-free leads to withdrawal bleeds (these are not periods)
What are the types of COC formulations?
Monophasic regimens: Same daily dose of EE and progestogen)
Phased regimens (Bi and triphasic): Dose varies to mimic cyclical endogenous hormone secretion
Biphasic: Constant EE, high progestogen in second half of the cycle
Triphasic: Increased EE in middle to decrease breakthrough bleeding plus stepwise increase in progesterone.
What are the common side effects of COCs?
Breakthrough bleeding (Increase oestrogen or progesterone dose)
Nausea (Decrease oestrogen dose or take at night with food)
Fluid retention, breast tenderness (Decrease oestrogen dose)
Chloasma (Avoid sun/use sun screen)
Although transient these side effects are the commonest reasons for discontinuing COCs.
Androgenic/anti-androgenic side effects:
Decrease in libido
Acne
Weight gain/loss
What are the rare and important side effects of the pill?
Enhanced coagulation (oestrogen dose related risk)
Increase in clotting leads to rise in risk of DVT/PE (2-3x increase), MI, stroke.
Oestrogen is associated with higher risk of breast cancer.
Small increase in risk of cervical cancer (causal link not established and may be behavioural in origin)
There is, however, a decrease in risk of ovarian and endometrial cancer.
Which patients should different methods of contraception be used in?
> 35 yo
Smoker
Obese
Clotting disorder
What are some benefits to taking COCs besides its main effect?
Decreased risk of PID, salpingitis, and ectopic pregnancy
Improvement in acne
Significant improvement in menstrual problems: cramps, heavy flow, endometriosis, premenstrual symptoms.
When should COCs not be used?
Pregnancy
History of VTE, stroke, CVD, major elective surgery, oestrogen-dependent cancer (breast/endometrium), migraine with “aura”
Hepatic disease
Women older than 35 yo, obese, smokers, HT, Diabetes
When should progestogen-only OCs be used?
Minipill
No oestrogen
Useful when oestrogen is contraindicated or not tolerated (breastfeeding, migraines with auras, >35 years old smoker, or other risk factors, before major surgery)
How does the minipill act?
Inhibits ovulation
Thickening and reduction in amount of cervical mucous impedes sperm penetration.
Endometrium thins decreasing implantation rates.
However, 30 - 40% of women on progestogen still ovulate.
What is important to note when taking progestogen only OCs?
Require meticulous compliance
Same time every day for 28/28 days
If 3 hours late use backup contraception.
How effective are Long Acting Reversible Contraception (LARCs)?
They are the most effective reversible form of contraceptive.
~20x more effective than OCPs
What are the potential complications of using LARCs?
Menstrual cycle disturbance is common with irregular bleeding but this decreases over time. (Levonorgestrel IUD often results in less bleeding and is used therapeutically.)
