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Treatment and Prevention of illness > Womens Health > Flashcards

Womens Health Flashcards

1
Q

Steroid Action

A

• 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 (↑& ↓)

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2
Q

Estrogen action

A

• 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.

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3
Q

Therapeutic estrogen-receptor modulators

A

• 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

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4
Q

Tamoxifen

A
  • Agonist in bone and uterus
  • Antagonist in breast
  • Used to treat breast cancer
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5
Q

Progestins

A

• 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)
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6
Q

Progesterone antagonists

A

» Mifepristone (RU 486) (mifeprex): PR antagonist
» Used to terminate pregnancy (along with prostaglandins to increase uterine contractions)
» Induction of labor after fetal death

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7
Q

Oral Contraceptives: History

A

• 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

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8
Q

Hormonal regulation of reproductive cycle

1 – Early Follicular Phase

A

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

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9
Q

Hormonal regulation of reproductive cycle

2 – Late Follicular Phase/Ovulation

A

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

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10
Q

Hormonal regulation of reproductive cycle

3 – Luteal phase

A

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

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11
Q

Hormonal regulation of reproductive cycle

4 – Menstruation

A

Pituitary hormone effects:
Low GnRH, LH, FSH

Ovarian hormone effects:
Progesterone and estradiol levels fall
• Causes endometrial arteries to constrict, resulting in
menstruation

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12
Q

Pregnancy

A
  • 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
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13
Q

Menopause

A
  • Occurs when all follicles depleted

* Decreased estrogen (and inhibin) → LH, FSH

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14
Q

Reproductive cycle physiology - summary

A

• 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

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15
Q

Methods of contraception

A 
• 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
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16
Q

Combined estrogen and progestogen

contraceptives

A

• 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

17
Q

Combined estrogen and progestogen

contraceptives

A

• 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

18
Q

Combined estrogen and progestogen

contraceptives - PK, schedules, monophasic vs multiphasic

A

• 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

19
Q

Combined estrogen and progestogen

contraceptives - ADR

A

• 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

20
Q

Combined estrogen and progestogen
contraceptives
• Contraindications and interaction

A

• 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

21
Q

Progestogen only contraception - oral

A

• 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

22
Q

Progestogen only contraception

Parenteral

A

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

23
Q

Copper IUD

A
  • “Coil” or “loop”
  • Plastic support with copper wound round it
  • Releases copper, prevents fertilization
24
Q

Emergency (“morning after”)

contraception

A

• 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

25
Q

Mifepristone (RU-486)

A
  • 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
26
Q

Therapeutic estrogen-receptor modulators

A

• 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)
27
Q

Menopause & HRT

A

• 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

28
Q

How do SERMs work?

A

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

29
Q

How do SERMs Achieve Selectivity?

A
  1. Differential SERM effects on estrogen
    receptor dimers – Either ERa, ERb homodimers or ab
    heterodimer
  2. Co-activator complex alters gene expression and
    response to SERM
  3. Differential effects on ER degradation (dependent on receptor subtypes, and co-activator complex)
30
Q

ideal SERM

A
  • strengthen bones
  • lower LDL cholesterol and raise HDL cholesterol
  • relieve hot flushes
  • reduce breast cancer risk
  • reduce uterine cancer risk
31
Q

Raloxifene (a newer SERM) good and bad effects

A 
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

Treatment and Prevention of illness (32 decks)

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