3.1 Gonadal Steroids & inhibitors Flashcards
_____ stimulates FSH and LH
FSH stimulates _____ cells initiating follicle growth & _____ production
LH acts on _____ cells to stimulate _____ as precursors to oestrogen
LH surge triggers ovulation and follicle conversion to corpus luteum which produces _____
GnRH, granulosa, oestrogen, thecal, androgens, progesterone
Give 3 general functions of oestrogen and progesterone
- Feedback
- Act on reproductive tract
- Act on other tissues
Give 3 main drug groups of the repro system
- Sex Steroids: oestrogens, progestogens, androgens
- Inhibitors and Antagonists
- Selective oestrogen receptor modulators (SERM)
Sex steroids are derivatives of _______.
Variations in ring groups lead to changes in what 2 things?
cholesterol
Changes in:
- function
- pharmacokinetics
What are the 3 main sex steroids, how many C’s in their core and give an example of each
Do progesterone, oestrogen and adrogens act on the same or different receptors?
DIFFERENT
Steroids are transported bound to ______ (EXCEPT ______) and albumin.
In the liver the sex steroid ______ is almost completly metabolised in one passage through
The metabolites are excreted in urine as ______ and ______
SHBG (SHBG = sex hormone-binding globulin), progesterone, progesterone, glucuronides, sulphates
What does progesterone bind to for transport in the circulation?
18% bound to Transcortin
80% bound to serum albumin
Note: does not bind to SHBP
Oestrogens contain ______ which bind to nuclear receptors. Once inside the nucleus _______ are activated. This results in a ______ response which differs in different tissues
Ligands, transcription factors, pleiotropic
How many isoforms of the oestrogen, progesterone and androgen receptors are there?
oestrogen: 2
androgen: 2
progesterone: 3
Give 3 naturally occuring oestrogens + state which is the main one
1) Oestrodiol (main endogenous oestrogen)
2) Oestrone
3) Oestriol
Give 5 comparisons of Ethinyloestradiol (synthetic) vs oestradiol (natural)
Ethinyloestradiol has:
1) higher oral bioavailability
2) less metabolism in liver and uterus
3) lower binding to hormone carrier protein SHBG
4) 100 fold increased oral potency (lower doses)
5) Less vaginal bleeding but more risk of thromboembolism
Give the most commonly used synthetic oestrogen
+ 2 oestrogen analogues derived from this
Ethinyloestradiol
+ Mestranol and Quinestrol
Give 2 other synthetic oetrogens that are from a non-human source
Equilin and Equilenin (from horses)
What is DES?
DES (Diethylstillbestrol) is a synthetic oestrogen which is a non-steroidal oestrogen. This means it is an agonist of the oestrogen receptor but isn’t derived from cholesterol
No longer used due to risk of congenital abnormalities
What is the main naturally occuring Progestogen in our body?
Progesterone
Give 2 benefits of progesterone derivatives compared to natural progesterone?
Fewer side effects and improved oral bioavailability
What are Progestins?
Progestins are synthetic compounds with progestogen activity.
(Do not necessarily have the 19C core)
Many androgen derivatives are referred to as progestins, why is this?
Because although ‘structurally’ these derivatives have a 19C core (androgen) they are able to bind and interact with the progesterone receptor and thus have progestogen activity!
Give 3 ways in which testosterone can be administed with examples
Implants: Testosterone
IM: Enenthate, Proprionate
Oral: Undecanoate, Mesterolone
Give 2 derivatives of Testosterone or 19-Norandrostane
Ethisterone and Dimethisterone
(display progesterone activity)
Give 4 general routes of administration for sex steroids
- Oral
- Transdermal
- Implants (subcutaneously or Intrauterine)
- Nasal
- Vaginal
- Intramuscularly
Give 4 actions and 4 side effects of oestrogen
(Hint: MR BCG is BENT)
Actions (MR BCG): Mildly anabolic, Retention of Na+ and H20, ⬇Bone resorption, ⬆Coagulability, Glucose tolerance impaired
S/E (BENT): Breast tenderness, Endometrial hyperplasia, Nausea+vomiting, Thromboembolisms
Give 4 actions and 4 side effects of progesterone
(FAMS AND I)
Actions (FAMS): Fluid retention, Anabolic, Mood changes, Secretory endometrium
S/E (AND I): Acne, Nause+vomiting, Depression, Irritability
Give 4 actions/side effects of testosterone
(2AAA)
- Male 2o sex characteristics
- Anabolic
- Aggression
- Acne
+ voice changes and metabolic adverse effects on lipids
What are the 2 types of OCP?
Incl the effectivness of each
1) oestrogen + progestogen (COCP) > 99% effective
2) progestogen only (POP) > 97% effective
What is the role of oestrogen is the COCP? (2)
1) Inhibits ovulation by suppressing FSH & LH
2) Alters secretions & cellular structure of endometrial lining to prevent implantation
What is the role of progesterone in the COCP and POP? (3)
1) Inhibits ovulation by suppressing LH
2) Thickens cervical mucous → impairs sperm movement
3) Alters endometrial lining to prevent implantation
Give 4 things we must consider when determing doses of the COCP?
(during clinical trials/ drug formulation)
1) dose must be minimum effective dose for whole population (dose > ED100)
2) inter-individual variation eg. body weight, absorption, metabolism and DDIs
3) oestrogen and progestogen doses arrived at empirically (by observation) and then effective o/p ratio is establised
4) reduce dose in trials until irregular bleeding or incidence of pregnancy
What are the 4 doses of oestrogens that can be prescribed in the COCP?
50, 35, 30, 20mg/day
What are the 2 main oestrogens found in the OCP?
Ethinyloestradiol and Mestranol
What are the 4 generations of Progestogens found in the OCP?
1st: norethynodrel
2nd: levonorgestrel, norethisterone
3rd: desogestrel, gestodene, norgestimate
4th: drospirenone (Yasmin: antimineralocorticoid, antiandrogen), norelgestromin (Evra: patch)
What is the dosage/cource length is reccomended for the COCP?
One tablet daily for 21 days followed by a 7 day pill free period
What are the 3 ways in which the COCP can be prescribed?
Define each
1) Monophasic: fixed amount of an oestrogen and a progestogen in each active tablet
2) Biphasic/Triphasic: varying amounts of the two hormones according to the stage of the cycle (commonly oestrogen constant progestogen increases)
3) ED (every day): Includes 7 days of placebo tablets
How do you decide which formulation of the COCP to prescribe?
Depends on patient… Start with Monophasic with the lowest possible risk of side effects (VTE)
If patient experiences spotting consider Biphasic
If patient likes routine/ is forgetful or on multiple medication consider the ED
Give an example of a Monophasic pill
20-35 micrograms of ethinyloestradiol plus levonorgestrel or norethisterone
How is the COCP metabolised
What can therefore be said about its drug-drug interactions?
Metabolised by cytochrome P450 (hepatic)
COCP’s efficacy is therefore reduced by enzyme inducing drugs
Give 2 drugs that may reduce the efficacy of the COCP?
Carbamazepine, phenytoin (enzyme inducing drugs)
What should a practitioner refer to when prescribing contraception?
UKMEC
Give 4 adverse effects of the COCP
What is the biggest risk factor of the COCP?
Breast cancer
What is the ‘Mini-pill’ and how is it taken?
What are the 2 formats that can be prescribed?
Progestogen-only pill: taken continuously 28 pills – no break
3 or 12 hour formats
What is the alternative pill when estrogens are contraindicated
Mini-pill / “progestogen-only pill”
What is the efficacy of the mini pill dependant on?
Efficacy dependent on the care of the user
List 4 Progestogens used in the mini pill
Levonorgestrel
Norethisterone
Etynodiol diacetate
Desogestrel
What is used for Depot provera?
Medroxyprogesterone acetate (MPA)
What is used for female implants and vaginal rings?
Etonogestrel
Give the Mode of Action of the mini pill
Adverse effect on cervical mucous (thickening)
Adverse effect on the endometrium (structural changes)
Some e.g. desogestrel, prevent ovulation
What is the disadvantage of the mini pill?
Poor cycle control
Some oestrogen production can lead to irregular bleeding
Give 3 options for emergency contraception
(Incl time frames and dosage)
1) Up to 72 hrs: Levonorgestrel (levonelle) 1.5mg
2) Up to 120 hrs: Ulipristal acetate (ellaOne) 30mg – progesterone receptor modulator
3) Past 120 hrs: Cu IUD
How does the Copper IUD act as an emergency contraceptive?
Causes inflammatory reaction in lining of womb
Give 2 instances when you would you prescribe HRT?
1) In post menopausal experiencing symptoms eg. hot flushes/sweats
2) May or may not be given in women with Osteoporosis
What is a contraindication for HRT?
Heart disease
What is the most common reason to prescribe oestrogen replacement therapy (ERT)
After hysterectomy
What is the main steroid used in ERT? (incl examples)
Oestradiol
e.g. valerate, enanthates, Micronised oestradiol 1-2mg/day, Premarin 0.625-1.25mg/day
What is the main steroid used in HRT? + 2 others
Medroxyprogesterone acetate (Provera)
Norethisterone
Duphaston
What are the 2 types of Combined HRT and explain each
When would you prescribe each?
1) Sequential combined: if women is still having some periods within the past year
* Continuous oestrogen given. Progesterone only at the end of each cycle- mimics usual cycle
2) Continuous combined: if patient has had no period in last year
* Constant oestrogen and progesterone
Give 4 risks of HRT
What must you advise all patients of HRT and why?
Advise all patients to attend all breast cancer screening due to the Increased risk of breast cancer
What is Mifepristone (RU486)?
Incl its MoA and state when it is most commonly used
An anti-progestogen!
It is a partial agonist to progesterone receptor which inhibits progesterones action. This sensitises the uterus to prostaglandins (e.g. mesoprostol)
Is used for medical termination of pregnancy, and induction of labour
What is Cyproterone acetate?
Incl its MoA and when it is most commonly used
An anti-androgen which is a Progesterone derivative
It exhibits a weak progestogenic effect as it is a partial agonist to progesterone receptor. It competes with dihydrotestosterone to bind to androgen receptor
Originally used in combined contraceptive pill (Dianette) BUT now used for acne
What is the risk of Cyproterone acetate and therefore what is its course length?
Risk of VTE so limited to 3 -18 months
What is SERM?
Selective oestrogen Receptor Modulators
Exhibits different potencies on different receptor isotypes
What is Raloxifene?
Give 3 positives and 1 negatives
A SERM
Positives
- Protects against osteoporosis due to oestrogenic effects on bone, lipid metabolism & blood coagulation
- Reduces risk of invasive breast cancer in postmenopausal women with osteoporosis
- No proliferative effects on endometrium & breast
Negatives: Increases hot flushes
Which SERMs is commonly used to induce ovulation + its MoA
Clomiphene (anti-oestrogen)➞ inhibits oestrogen binding to anterior pituitary which inhibits negative feedback, resulting in increased GnRH and FSH, LH
What is Tamoxifen and give 2 common clinical uses
Tamoxifen is SERM which is an anti-oestrogen
Primarily used intreatment of ER+ breast cancer and can alos be used to induce ovulation
