3 Reproductive Hormones Flashcards
Natural & Synthetic Estrogens
Progesterone & Synthetic Analogues
- progesterone & 19-nortestosterone derivatives
Combined Oral Contraceptives
- pharmacological actions of estrogen & progestogens
- risk-benefit ratios
Progesterone only Contraceptives
Post-coital Emergency Contraceptives
Estrogen Antagonists
SERMs & Anti-estrogens
- use & adverse effects
Anti-progestogens
- combination w/ prostanoids for abortion
Estrogen Types
- principal source: ovaries
- estradiol, synthesized by granulosa cells
- converted to estrone & estriol in liver
- placenta; estrone & estriol
- adipose tissue; estrone
Steroidal
- Mestranol
- Ethinylestradiol
Non-steroidal
- Diethylstilbestrol
- Chlorotrianisene
*ethinyl sub at C17 position greatly inc oral potency by inhibiting first-pass hepatic metabolism
Estrogen Mechanism of Action
- Estrogen receptors in nucleus: ER-a & ER-B
- ER-a: female reproductive tract (uterus, vagina & ovaries), mammary glands, hypothalamus, endothelial cells & vascular smooth muscle
- ER-B: higher density in prostates & ovaries
- cell proliferation, migration & differentiation
- progesterone dec ER expression in reproductive tract
- prolactin inc ER # in mammary gland, but NOT in uterus
Natural Estrogen Pharmacokinetics
- well absorbed oral
- rapidly metabolised in liver by conjugation
- variable amount of enterohepatic cylcing
- excreted in bile & urine
- oral; micronized or conjugated estrogens
- i.m.; sustained release
- transdermal patch; absorb from skin
- local effect; vaginal cream or pessaries
- > 97% bound to plasma SHBG
Ethinylestradiol Pharmacokinetics
- rapid & complete via oral
- 50% bioavailability
- > 95% bound to plasma albumin
- t-1/2; 12 hrs
- metabolised by 2-hydroxylation (CYP450) & conjugation by glucuronidation or sulphation
- mestranol undergoes rapid hepatic demethylation to ethinyl estradiol activities
Progestogens
- progestins, progestational agents, progestagens, gestagens or gestogens
- progesterone from corpus luteum during 2nd half of menstrual cycle
- from placenta / adrenal cortex / testis
- bound to transcortin & albumin, NOT to SHBG
- orally inactive due to rapid metabolism in liver
- excreted in urine; hydroxylated metabolites, sulphate or glucuronide conjugates
Mechanism of Action:
- specific PR-A & PR-B receptors
- similar as estrogen-ER interaction
- female reprod tract, mammary gland, CNS & pituitary
- presence of adequate receptors depends on estrogen priming
- PR-A acts as transcriptional inhibitor of other steroid receptors
- PR-B mediates stim activity
Progesterone derivatives
- 17-hydroxyprogesterone acetate derivatives
- highly selective w/ activity similar to progesterone
- retarded metabolism & improved oral bioavailability
- Hydroxyprogesterone caproate (i.m.)
- Medroxyprogesterone acetate (oral or i.m.)
- used in conjunction w/ estrogens for menopausal hormone replacement therapy
- for selective progestational effects
Testosterone derivatives
- 19-nortestosterone derivatives (C19 CH3 replaced by H)
- norethisterone, norethynodrel, ethynodiol
- less selective than progesterone esters
- varying degrees of androgenic, estrogenic, antiestrogenic activities
- 13-ethyl derivaties of 19-nor
- lower androgenic activity
- Levonorgesterl, Gestodene, norgestimate & desogestrel
- oral (1-3 days), contraceptive
Combined Oral Contraceptive Pill
Monophasic
- fixed amount in each pill for 21 days, then a 7-day pill free period
- Estrogen (<50µg)
- ethinylestradiol; mestranol
Biphasic / Triphasic
- varying amounts of drugs for 21 days
- reduce total amount of steroids
- mimic natural estrogen / progestogen ratio
- progesterogen (lowest conc.)
- Levonorgestrel
- Norethisterone
- Gestodene
- Desogestrel
- Norgestimate
- missed if 12 hrs late
Hypothalamus-pituitary axis:
- mainly by preventing ovulation
- synergy btwn estrogen & progestogen
- estrogen upregulates progesterone receptors & enhances sensitivity to progesterone
- non-physiological mech from prolonged administration
Female Reproductive Tract:
- reduce likelihood of conception & implantation
- reduce transport of sperm & ovum in upper genital tract (fallopian tubes)
- change endometrium -> less receptive to implantation
- thicken cervical mucus (reduce sperm penetration)
- overall contribution of uterine change less significant than suppression of ovulation
Clinical Use:
- highly effective (>99%)
- current low dose has minimal risk
- dec menstrual flow (lighter, shorter periods)
prevent iron deficiency anaemia
improve existing iron deficiency anaemia
decrease menstrual cramps
- protect against ovarian & endometrial cancer
- dec benign breast disease & ovarian cysts
- reduced risk of pelvic inflammatory diseases
Side Effects:
- mild & transient
- high BP, amenorrhea, breast fullness or tenderness, nausea, dizzy, vomit
- mood change (depression or loss of libido)
- acne, weight gain & hirsutism
Effects on Cardiovascular System
Estrogen:
- Vasodilation
- inc NO production w/in mins
- inc inducible NO synthase & inc prostacyclin
- Retention of water & salt
- lowers osmotic threshold for stim & release of AVP
- Na+ retention inc when combined estrogen + progesterone
- inc plasma level of angiotensinogen
- stim effect on liver
- Elevate serum triglycerides & reduce total serum cholesterol
- inc HDL w/ reduction in LDL -> atherosclerosis reduced
- inc coagulability of blood
- significant inc in fibrinogen & blood clotting factors (VII to X) & inhibit antithrombin III formation -> inc venous thromboembolism
Serious Adverse Effects of Combined Oral Contraceptive Pills
- Venous thromboembolism
- related to estrogen dose
- reduced risk w/ 2nd gen pill
- debatable inc risk w/ 3rd gen pill
- changes in platelet functions & fibrinolytic system
reduced venous blood flow
endothelial proliferation in vv & aa
inc coagulability of blood -> inc incidence of thrombosis - Myocardial infarction / stroke
- higher risk for
women
sedentary & obese
history of preeclampsia, hypertension, diabetes or hypercholesteremia
smoker
over 35 years old - thrombotic mech rather than atherogenic
- lower incidence w/ stroke
- Hepatic adenoma & hepatocellular carinoma
- rare & debatable
- Breast cancer
- no significant inc in population
- inc risk in younger women
- Cervical cancer
- debatable but show 2x risk
Contraindications & Drug Interactions of Combined Oral Contraceptive Pills
Contraindications:
- liver disease or tumor
- ischemic heart disease or stroke
- blood clotting disorders
- smoker aged 35 or older
- carcinoma of breast or genital tract
- diabetic
- headaches (migraine)
- high BP (>180/110)
- undergone major surgery
Drug Interactions:
- Enzyme inducers
- reduce effectiveness by inc estrogen metabolism by CYP450
- e.g. rifampicin, barbiturates, anticonvulsants (phenytoin)
- Antibiotics
- reduce effectiveness by dec enterohepatic recirculation of steroid hormones through disturbance of bacterial flora of gut
- e.g. ampicillin, tetracycline
Pharmacokinetics of ethinylestradiols & progestogens & interaction w/ enzyme-inducing drugs
See lecture, too complex
Transdermal Combined Contraceptive
- Ortho Evra
- delivers 150µg of norelgestromin & 20µg ethinylestradiol daily to systemic circulation
- bypasses GI tracts
- 3 week patch cycle, 4th week free
Side Effects:
- application site reactions
- breast discomfort & dysmenorrhea
