Womens Health Flashcards
Steroid Action
• Receptors
– Estrogens & androgens bind to intracellular receptors
» Estrogen (ER), Androgen receptor (AR) and Progesterone receptors (PR)
– ER or AR dimerize, and translocate to nucleus
• Recognise particular DNA sequence called “response elements”:
» ERE (estrogen response element), ARE (androgen response element), PRE (progesterone response element)
– regulate gene transcription (↑& ↓)
Estrogen action
• Estrogens act as signaling molecules by interacting
with specific target cells.
– Include tissues of the breast, uterus, brain, heart, liver, and bone.
– ER modulation used in contraception; treatment of peri- and post-menopausal problems (Hormone Replacement therapy); and treatment and prevention of breast cancer
• These target cells have estrogen receptors.
– There are two estrogen receptors that are of the nuclear
hormone class and which act in the cell’s nucleus:
ER α and ER β.
• The receptor undergoes dimerization in order for it to
have increased affinity for ERE’s, and regulate gene expression.
Therapeutic estrogen-receptor modulators
• A range of drugs with different actions at the estrogen receptor are available
• Estrogen-receptor agonists
– Natural and synthetic estrogens
– Hormone replacement therapy (HRT) and contraception
• Specific estrogen receptor modulators (SERMs)
– Different medicines have selectivity for different tissues
Tamoxifen
- Agonist in bone and uterus
- Antagonist in breast
- Used to treat breast cancer
Progestins
• Interact with PR to mimic the stimulatory affects of progesterone
• Physiological Target: Reproductive Tract
- Decreases estrogen-driven endometrial proliferation
- Establishment and maintenance of pregnancy
- Common Uses:
- Oral contraceptives
- HRT to limit estrogen’s effects on the endometrium
- Uterine Bleeding disorders
- Premature labor (decrease uterine contractions)
Progesterone antagonists
» Mifepristone (RU 486) (mifeprex): PR antagonist
» Used to terminate pregnancy (along with prostaglandins to increase uterine contractions)
» Induction of labor after fetal death
Oral Contraceptives: History
• 1950: Gregory Pincus et al (progesterone prevents ovulation)
• 1959: 1st pill appeared in USA
• 1960: mini pill (progesterone alone)
• 1970: Introduction low dose or second generation of OC’s
• 1980: biphasic or triphasic regimens
• 1990: 3rd generation OCs
e.g, norgestimate 0.25mg or desogestrel 0.15 mg)
ALL OF THESE RELY ON THE ROLE OF SEX-STEROIDS IN THE NORMAL REGULATION OF THE FEMALE REPRODUCTIVE CYCLE
Hormonal regulation of reproductive cycle
1 – Early Follicular Phase
Pituitary hormone effects:
FSH stimulates several follicles to grow, and stimulates estradiol secretion
Ovarian hormone effects:
Follicles produce low levels of estradiol which
• Causes endometrial arteries to constrict, resulting in menstruation
• Inhibits LH secretion
• Stimulates FSH secretion
Hormonal regulation of reproductive cycle
2 – Late Follicular Phase/Ovulation
Pituitary hormone effects:
FSH stimulates one follicle to further develop
LH surge stimulates ovulation from that follicle
Ovarian hormone effects:
Follicles produce increasing levels of estradiol which
• Stimulates GnRH secretion by hypothalamus,
• With GnRH drives LH levels to spike, causing ovulation
• Causes the endometrium to further develop
Hormonal regulation of reproductive cycle
3 – Luteal phase
Pituitary hormone effects:
LH stimulates development of a corpus luteum left behind after ovulation
Ovarian hormone effects:
The corpus luteum secretes progesterone and estradiol which
• Blocks GnRH secretion by the hypothalamus and LH and FSH secretion by the pituitary.
• Causes the endometrium to further develop
Hormonal regulation of reproductive cycle
4 – Menstruation
Pituitary hormone effects:
Low GnRH, LH, FSH
Ovarian hormone effects:
Progesterone and estradiol levels fall
• Causes endometrial arteries to constrict, resulting in
menstruation
Pregnancy
- If implantation occurs – blastocyst produces hCG (human chorionic gonadotropin) which supports continued secretion of progesterone by the corpus luteum until placenta takes over
- Progesterone crucial during pregnancy:
- Maintains decidua (lining of the uterus)
- Promotes blood vessel growth
Menopause
- Occurs when all follicles depleted
* Decreased estrogen (and inhibin) → LH, FSH
Reproductive cycle physiology - summary
• Steroid hormones are important in the determination of sexual characteristics and in reproduction
– The key female sex steroids are estrogen and progesterone
• Estrogen receptor modulation is an important therapaeutic strategy
– contraception, regulation of peri- and post-menopausal changes, and in the treatment of steroid-dependent breast cancer
• The female reproductive cycle involves a complex hormonal interplay between the hypothalamus, the pituitary, the ovaries and the uterus
– Understanding the role of hormones in regulating the normal function of the reproductive cycle forms the basis of female contraceptive treatments
Methods of contraception
• Mechanical – Condoms, diaphragms, intrauterine devices – Some can be combined with chemical spermicide » Essential with a diaphragm » Nonoxynol 9 - surfactant • Hormonal – Several routes of administration » Orally (p.o.) » Depot formulation for i.m. injection » Transdermal patch » Vaginal ring » Intra uterine devices
Combined estrogen and progestogen
contraceptives
• 99% effective (combination more effective than either E2 or PG alone) Pills, Patch or Vaginal Ring
• Estrogens: ethinyl estradiol or mestranol
• Progestins: through the different generations of these drugs the aim has been to derive a form with potent progestational and antiestrogenic effects on the endometrium with a strong antigonadotropic effect, but without androgenic or mineralocorticoid effects.
– norethisterone (norethindrone in US) 1st generation
– norgestrel or levonorgestrel, 2nd generation
» Agonists at androgen receptor
– desogestrel, gestodene, norgestimate
» “3rd generation” - less androgen activity
» Potential for increased incidence of venous thromboembolism, but FDA rulethat there is not sufficient evidence to warrant withdrawal
̶ drospirenone: 4th generation, anti-androgenic & anti-mineralocorticoid
Combined estrogen and progestogen
contraceptives
• Mechanism – multiple – not fully understood!
– Suppress GnRH, LH and FSH release
» At hypothalamic & pituitary level
– Progestin inhibits estrogen-induced LH “surge” & inhibits ovulation
» Estrogen upregulates PGR, increasing negative feedback by the progestogen (synergy)
– include progestin because “estrogen only” promotes endometrial growth
– link to endometrial cancer if used on own
Combined estrogen and progestogen
contraceptives - PK, schedules, monophasic vs multiphasic
• PK
– Phase 1: Extensive first pass by intestinal and hepatic P450 (3A4)
– Phase 2: Sulfation & glucoronidation, followed by biliary secretion
» Conjugation prevents enterohepatic recirculaton
• Schedules:
– 21 days drug, 7 days placebo
– long cycles eg of 42 + 7 days also possible to reduce frequency of menstrual bleeding
– Endometrium may decay and bleeding occurs during placebo period but bleeding less because reduced endometrial proliferation
• Monophasic vs Multiphasic
– monophasic – dose of estrogen and progestin doesn’t vary
– biphasic, triphasic forms available
» Biphasic: only progestin dose varies
» Triphasic: 3 different dose combinations
Combined estrogen and progestogen
contraceptives - ADR
• ADR (Estrogen)
– Fluid retention and hypertension (acute)
– Risk of endometrial cancer increased (long term use)
• ADR (Progestogen)
– Headache, nausea & vomiting, lower back pain
• ADR (Combination)
– Hypertension
– Thromboembolism
» Potential for DVT, pulmonary embolism, M.I., stroke
» Incidence increases ~30% (from ~10 per 100,000)
» Greater risk if smoker (predisposed to thromboembolism)
» Stop drug immediately if suspect this (eg chest pain, breathlessnes, swelling in leg)
– Cancer
» Some cancer types are driven by estrogen (eg some breast tumours)
– Was controversial – now thought risk relatively small (for combination)
» There is a risk of benign liver tumour (hepatocellular adenoma)
» Reduced risk ovarian cancer
Bottom line: widely taken well tolerated
Combined estrogen and progestogen
contraceptives
• Contraindications and interaction
• Contraindications
– if at risk of cardiovascular, thromboembolic or malignant disease. e.g.
» History of thromboembolism, myocardial infarction,
» familial hyperlipidemia
» Smoking and > 35 years
» Estrogen dependant cancers (e.g. breast)
– Pregnant
• Interactions
– Drug which induces P450 can lead to contraceptive failure (i.e pregnancy!) see PK
» Riampicin
» Phenytoin
» Phenobarbitol
» St John’s wort
Progestogen only contraception - oral
• Also know as the “mini pill”, POP (progestin only pill)
– Levonorgestrel, norethisterone, Desogestrel, ethynodiol
– Must be taken regularly (should be taken at the same time each day)
– Other routes – parenteral and intra-uterine
• Useful where estrogen contraindicated
– Hypertension, Smoking, Diabetes
• Mechanism
– Inhibition of GnRH release
– Not quite as efficacious as combination (no opportunity for synergy)
– Some ovulation can still occur but still ~98% successful
» Possibly because PG inhibits endometrial proliferation, preventing implantation?
– Usually no menstruation, but may occur irregularly
• ADR
– Breakthrough bleeding can occur
Progestogen only contraception
Parenteral
Depot injections
• Medroxyprogesterone
– Long t1/2 ~30hr (i.v.)
– Aqueous depot formulation for i.m. injection every ~12 weeks
• Norethisterone
– Oil depot formulation used for short term contraception
– Also used to treat heavy periods
• Both may have problems with return to full fertility (as these are slow release formulations)
• Subdermal implant
– Levonorgestrel
– Fertility restored on removal
– Irregular and prolonged bleeding can occur
• Intra-uterine device (IUD)
– Levonorgestrel
– Prevents endometrial thickening
» Because of “proliferative to secretory switch” (hence could consider it topical)
– Fertility restored on removal
– Irregular and prolonged bleeding can occur
– Dysmenorrhoea (period pain) less than with copper IUD
Copper IUD
- “Coil” or “loop”
- Plastic support with copper wound round it
- Releases copper, prevents fertilization
Emergency (“morning after”)
contraception
• Levonorgestrol – high single dose, blocks LH surge
– Prevents ovulation & implantation
– Useful for up to 72 hours after intercourse
• Ulipristal (SPRM)
– Useful up to 120 hr after intercourse
Not effective after implantation
Mifepristone (RU-486)
- Progesterone receptor antagonist
- Used for abortion
- Blocks progesterone receptor, causing decay of decidua and embryo dies and detaches
- Maybe used in combination with misoprostol (prostaglandin) to induce contractions
- ADR: Risk of serious bleeding, should only be administered under
Therapeutic estrogen-receptor modulators
• A range of drugs with different actions at the estrogen receptor are available
• Estrogen-receptor agonists
– Natural and synthetic estrogens
– Contraception, Hormone replacement therapy (HRT)
• Specific estrogen receptor modulators (SERMs)
– Medicines with selectivity for different tissues
- raloxifene (agonist in bone, antagonist in breast and uterus)
- tamoxifen (agonist in bone and uterus, antagonist in breast)
Menopause & HRT
• Occurs when all follicles depleted
• Decreased estrogen and inhibin → LH, FSH
– estrogen synthesis depends on aromatase in adipose tissue, hence less estrogen (previous source of granulosa cells in follicles not present)
• Symptoms – hot flushes, vaginal dryness
• HRT - Estrogen + progestin to prevent risk of endometrial cancer
• ADR
– Increased risk of coronary heart disease, breast cancer, stroke and pulmonary embolism
– Hence recommend low does for short period
• Reduced risk of hip fracture from osteoporosis
How do SERMs work?
Multiple theories
1. Tissue-specific pattern of estrogen receptors
– Two receptors identified (ERa and ERb)
– SERM’s have different affinities for ERa homodimers, ERb homodimers and ERa ERb heterodimers
2. Tissue-specific pattern of co-regulator expression
– The pattern of genes activated by ER activation is regulated by the expression of co-regulator proteins
– Co-regulator repertoire varies from tissue to tissue (hence genes activated in bone are different from those in breast)
– Co-regulator recruitment may be ligand-dependent, thus a ligand may recruit co-activators specific to one tissue but co-repressors specific to another
3. Effects on ER stability and degradation
– Some ER antagonists have been shown to increase the rate of ER degradation
How do SERMs Achieve Selectivity?
- Differential SERM effects on estrogen
receptor dimers – Either ERa, ERb homodimers or ab
heterodimer - Co-activator complex alters gene expression and
response to SERM - Differential effects on ER degradation (dependent on receptor subtypes, and co-activator complex)
ideal SERM
- strengthen bones
- lower LDL cholesterol and raise HDL cholesterol
- relieve hot flushes
- reduce breast cancer risk
- reduce uterine cancer risk
Raloxifene (a newer SERM) good and bad effects
Good effects • Strengthens bones • Lowers LDL cholesterol • Reduces risk for invasive breast cancer • Fewer uterine cancers than tamoxifen • Fewer blood clots than tamoxifen
Bad effects • Hot flushes • Blood clots • Leg cramps • Teratogenic (can cause developmental abnormalities and birth defects)
- Antagonist activity in breast & endometrium does not appear to increase risk of endometrial cancer
Used for treating breast cancer - Agonist activity in bone decreases bone resorption. Used to delay and prevent progression of osteoporosis in post- menopausal women
