Pharma Of Sex Hormones And Antagonists

Front 1

What is the most important of oestrogens? (3)
what controls it?
how is it synthesized (3)

Back 1

• 17B-estradiol (active), estrone & estriol (less active)

• FSH: regulates synthesis & secretion

Synthesis
• precursor: testosterone,
• key enzyme: aromatase
• metabolism of 17B-estradiol to estrone & estriol

Front 2

where are estrogens produced? (5)

Back 2

• ovaries: estradiol
• ovarian follicles (before ovulation);
• corpus luteum (after ovulation)
• placenta (pregnancy)
• estrone & estriole in liver/peripheral tissues, from estradiol

Front 3

mechanism of action of estrogens

Back 3

Estrogen + ER (of superfamily of nuclear receptor) ->
ER conformation change ->
translocation to nucleus ->
bind to estrogen response element in target gene -> recruit co-activators ->
initate gene transcription ->
specific hormonal effect

Antagonist: same process as estrogen, except co-repressors (not co-activators) recruited, and gene transcription is REDUCED.

Front 4

admin (5)/absorption of estrogens (1)

Back 4

• estradiol: 1st pass (low bioavail. & hepatic effects): micronized prep for rapid absorption post oral intake
• ethinyl estradiol: reduce 1st pass
• conjugated equine estrogen: sulfate esters of estrone/other estrogens, metabolized to active form
• IM: aqueous & oil-based preparations
• transdermal: slow sustained, avoid 1st pass

• enterohepatic recirculation: conjugation in liver -> excrete into intestine -> hydrolysed in gut -> reabsorb

Front 5

effect of estrogens (4)

Back 5

- female repro/breast tissues
- bone: +ve effect on bone mass. ↓osteoclast apoptosis, ↓resorption of bone
- Lipids: ↑HDL, ↓LDL; ↑synthesis of TG
- Coagulation: ↑clotting factors (hepatic coagulation)

Front 6

limitations of estrogens (related to dose) (4)

Back 6

- stimulate endometrial growth (risk: hyperplasia, ↑uterine bleeding risk)
- ↑ Ca breast, Ca endometrium
- ↑ thromboembolism
- nausea, breast tenderness, migraine, HT

Front 7

clinical uses of estrogens (6)

Back 7

- replace estrogen deficiency (failed ovaries, menopause)
- primary hypogonadism
- development of sec. sexual characteristics (11-13 y/o)
- stimulate growth & bone development
- Progestin/birth control/HRT
- tx osteoporosis

Front 8

what are SERM (selective estrogen receptor modulators) and anti-estrogenic:
- examples of both (3 SERM, 2 anti)

Back 8

- SERM: tamoxifen, raloxifene, toremifene
- anti-estrogens: clomiphene, fulvestrant

Front 9

Tamoxifen
what is it (1)
clinical uses (2)
limitations (1)
side effect (4)

Back 9

- partial agonist/inhibitor of ER
- tx & chemoprevention of Ca breast in high risk grp.
- reduce contralateral ca breast
- no further improvement after 5 yrs
- SE: hot flush, nausea, vomiting, infertility

Front 10

Raloxifene
properties (3)
clinical uses (2)

Back 10

- parial estrogen agonist/antagonist (SERM) in SOME target tissue
- effects similar to estradiol on lipids/bones
- NO effect on breast & endometrium

- prevent osteoporosis in postmenopausal
- prophylaxis of ca breast in high-risk ♀ (less useful than tamoxifen)

Front 11

fulvestrant's properties (2)

Back 11

- pure anti-estrogen
- tx tamoxifen resistant ca breast

Front 12

estrogen synthesis inhibitors (2)
examples (3)

Back 12

- aromatose inhibitor
(↓estrogen ∵ aromatose in synthesis of estradiol)
- Tx Ca breast

- exemestane, letrozole, anastrozole

Front 13

Progestins:
most important
controlled by?
produced by? (2)
levels (3)

Back 13

- progesterone

- LH: regulates synthesis and secretion

- corpus luteum. placenta in pregnancy

- low level in follicular phase,
higher level in luteal phase
much higher during pregnancy

Front 14

mechanism of action of progestins (3)

Back 14

- PR (superfamily of nuclear receptor: PR-A, PR-B)
- hormone + PR -> PR conformation change -> dimer -> translocation to nucleus -> bind to prog. response element (in target gene) -> recruit co-activator/co-repressor -> modify gene transcription -> specific hormonal effect
- PR-A or PR-B + coactivators & corepressors -> various effects (↑/↓ gene transcription)

Front 15

admin (3)/absorption (4)

Back 15

- ester: ↓hepatic metabolism
- oil-based: for IM injection
- implants/depot: slow release (long-term tx)

- 1st pass of progesterone: low bioavailability, hepatic effects (micronized prep for rapid absoprtion)
- free progesterone elimination t1/2: 5 minutes
- highly protein bound -> longer half-defect
- synthetic progestins: similar effect to progesterone

Front 16

effects of progestins (3)

Back 16

- luteal phase of menstrual cycle
- Repro: maintain pregnancy, ↓ estrogen-stimulated endometrial proliferation
- ↑LDL/↓HDL (opposite of estrogens on lipid profile)

Front 17

clin uses of progestins (4)

Back 17

- contraceptin: alone, or with estrogen
- HRT in postmenopausal
- abnormal uterine bleeding (↓estrogen's effect on endometrial growth & hyperplasia
- palliative for metastatic ca endometrium

Front 18

what are anti-progestins (2)
SE (1)

Back 18

mifepristone
- block uterine PR -> detach blastocyst -> ↓hCG -> ↓ progesterone by corpus luteum -> loss of blastocyst (can't maintain pregnancy)
- mifepristone combined w. misoprostol (PG): termination of early pregnancy (misoprostol: contraction of uterus, expulsion of fetus)

SE: vaginal bleeding

Front 19

what are androgens:
- most important
- regulation
- levels in people
- produced by

Back 19

- testosterone, dihydrotestosterone

- gonadotrophins (LH). *testosterone inhibits LH secretion in men

- declines after 50 in men.

- 95% Leydig cells of testis, 5% by adrenals
- Testosterone -> DHT (5a-reductase)
- Testosterone -> estradoil (aromatase)
- smaller amount in women (frm ovaries, adrenals)

Front 20

mechanism of action of androgens

Back 20

androgen receptor (nuclear):
testosterone & DHT major agonists for androgen receptor

- Hormone + AR -> AR conf. change -> dimer -> translocation to nucleus -> bind to androgen response elemtn in target gene -> recruit co-activators/co-repressors -> initate gene transcription
↑/↓ gene transcription

Front 21

admin (3)
absorption (2)
of androgens

Back 21

- IM injection of ester form: hydrolysis to release testosterone. (bypass hepatic metabolism)
- alklyated androgens ↓ hepatic metabolism
- transdermal delivery systems: patch, gel

- absorb rapidly -> inactive (and some active) metabolites in liver
- 1/6 avail. in active form: difficult to control amnt of active & inactive metabolites

Front 22

effects of androgens

Back 22

anabolic effect
development/growth of male repro organs

Front 23

clin uses of androgens (4)

Back 23

- androgen replacement tx in men: secondary sex characteristics -> puberty/enhance growth (use IM injection of long acting ester form)
- gynecological disorders: danazol for endometriosis, for chemo of ca breast in premenopausal
- anabolic steroid/androgen abuse in sports (↑strength & aggressivness)
- aging: ↑lean body mass & hematocrit, ↓bone turnover

Front 24

anti-androgens (2)
describe them (2)

Back 24

Androgen receptor antagonists (flutamide etc)
-block testosterone receptor -> ↑LH secretion -> ↑testosterone -> counteract effect of antagonist
- in conjunction w. blocking GnRH to tx Ca prostate

5a-reductase inhibitors (finasteride & others)
- block coversion of testerone to dHT
- treat BPH

Front 25

why must we give postmenopausal hormonal therapy (what happens when you go on menopause) (3)

Back 25

After menopause: ↓female hormones by ovaries
- ↑bone loss, ↑fractures (vertebral, hip, wrist)
- ↑plasma cholesterol (↑atherosclerosis, ↑CVS disease)
- postmenopausal: hot flush, insomnia

vasomotor sx, osteoporosis, vaginal dryness, UG atrophy

Front 26

Give an example of HRT: (3)
are there any proven benefits?

Back 26

continuous/cyclic
- conjugated estrogens, MPA (medroxyprogesterone acetate) & other progestins
- estrogen + progestin (menopausal, +uterus)
- estrogen (menopause, hyster., no endometrial prob)

- NO: small ↑Ca breast, ↑CVS disease. ↓Ca colon, ↓osteoporosis

Front 27

what is homornal contraception (3)

Back 27

- producuing temporary, reversible state of infertility
- combined pill: estrogen-progestin
- mini pill: progestin-only

Front 28

describe hormone 'flow' of female repro system (5)

Back 28

Hypothalamus: GnRH ->
stimulate anterior pituitary: FSH, LH ->
FSH stimulates Graafian follicle -> oestrogen
LH stimulates corpus luteum -> progesterone
oestrogen/progesterone inhibits ant. pituitary

Front 29

admin (1) and MoA of combined pill (estrogen + progestin) (6)

Back 29

- take 21 consecutive days, with 7 day break

- ↑neg. feedback: selectively inhibit pituitary function
- ↓FSH release: ↓development of ovarian follicle
- ↓LH release: prevent ovulation
- changes cervical mucus in uterus
- change motility & secretion in uterus
- ↓conception, implantation

Front 30

admin (1) and MoA of progestin-only contra (3)

Back 30

continuously for 28 days, w/o break

- inhibit hypothalamus, slow frequency of GnRH pulse generator. Inhibits LH release; prevents ovulation
- cervical mucus thickens, ↓sperm penetration
- endometrial alterations, ↓implantation