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
