HUF 2-34&35 Pharmacology of reproductive hormones Flashcards
Estrogens
- Principal source: ovaries
- Estradiol by granulosa cells
- Converted to estrone and estriol in liver
- Placenta: estrone, estriol
- Adipose tissue: estrone
- Estradiol > estrone > estriol
Synthetic estrogens
- Steriodal: Menstranol, Ethinylestradiol
- Non-steroidal: Diethystilbestrol, Chlorotrianisene
- Inhibit first-pass hepatic metabolism
=> ↑ oral potency
Mechanism of action of estrogens
- Estrogen receptors in nucleus: ERα, ERβ
- ERα: female reproductive tract (uterus, vagina, ovaries), mammary glands, hypothalamus, endothelial cells, vascular smooth muscle
- ERβ: prostates, ovaries
- Cell proliferation, migration, differentiation
- P4 ↓ ER expression in reproductive tract
- PRL ↑ ER numbers in mammary gland but not in uterus
PK of natural estrogens
- Well absorbed orally
- Plasma SHBG
- Metabolised in liver by conjugation
- Variable amount of enterohepatic cycling
- Excreted in bile and urine
- Oral: micronised or conjugated estrogens (Valerate, Cypionate)
- IM injection: sustained release
- Absorted from skin: transdermal patches
- Local effect: vaginal cream, pessaries
PK of Ethinylestradiol
- Rapidly and completely absorbed orally
- 50% bioavailability
- > 95% bound to plasma albumin
- t1/2 = 12hr
- Metabolised by CYP45 (2-hydroxylation), conjugation by glucuronidation or sulphation
- Mestranol: rapid hepatic demethylation to ethinylestradiol for activites
Progestogen
- P4 from corpus luteum during 2nd half of menstrual cycle
- Placenta / adrenal cortex / testis
- Bound to transcortin and albumin but not to SHBG
- Orally inactive (rapid metabolism in liver)
- Hydroxylated metabolites => glucuronidation, sulphation
- Excreted in urine
Mechanism of action of progestogens
- PR-A, PR-B
- Similar as estrogen-ER interaction
- Female reproductive tract, mammary gland, CNS, pituitary
- Presence of adequate receptors depends on estrogen priming
- PR-A: transcription inhibitor of other steroid receptors
- PR-B: mediates stimulatory activities
P4 derivatives
- 17-hydroxyprogesterone acetate derivatives
- Hydroxyprogesterone caproate, Medroxyprogesterone acetate
- Highly selective with a spectrum of activity similar to P4
- Retarded metabolism and improved oral bioavailability
- Conjunction with estrogen => Menopausal hormone replacement therapy
- Selective progestational effect is desired
Testosterone derivatives
- 19-Nor testosterone derivatives
- Norethisterone, Norethynodrel, Enthynodiol
- Less selective than P4 esters
- Varying degrees of androgenic, estrogenic, antiestrogenic activities
- 13-ethyl derivatives of 19-Nor
- Lower androgenic activity
- Levonorgestrel, Gestodene, Norgestimate, Desogestrel
- Orally active, 1-3 ays duration
- Oral contraceptive
Combined oral contraceptive
Monophasic
- Estrogen, ethinylestradiol (Mestranol)
- Fixed amount in each pill for 21 days + 7-day pill free period
Biphasic / Triphasic
- Progestogen (loweret conc.): Levonorgestrel, Norethisterone, Gestodene, Norgestimate, Desogestrel
- Varying amounts of active ingredients for diff. times during 21 day
- ↓ Amount of steroids
- Mimic natural estrogen / progestogen ratio
Hypothalamus-pituitary axis
- Prevent ovulation
- Synergism between estrogens and progestogen
- Estrogen upregulated progestogen receptors
=> ↑ Sensitivity to P4 - Prolonged administration
=> non-physiological mechanisms - -ve. feedback to LH and FSH => NO mid-cycle LH surge
Effects of combined oral contraceptives on female reproductive tract
- ↓ Likelihood of conception and implantation
- ↓ Transport of sperm and ovum in upper genital tract (fallopian tubes)
- Change in endometrium => less receptive to implanatation
- Thicken cervical mucus (↓ sperm penetration)
Benefits of combined oral contraceptives
- Highly effective (>99%)
- Low dose: minimal health risks except in women with predisposing factors
- ↓ Menstrual flow (lighted, shorter periods)
- Prevent iron deficiency anemia
- Improve existing iron deficiency anemia
- ↓ Menstrual cramps
- Protect against ovarian and endometrial cancer
- ↓ Benign breast disease and ovarian cysts
- ↓ Risk of pelvic inflammatory diseases
Minor unwanted effects of combined oral contraceptive-
- Mood changes: depression, loss of libido
- Nausea, vomiting, dizziness
- Breast fullness, tenderness (mastalgia)
- Amenorrhea, bleeding / spotting
- High BP
- Acne, weight gain, hirsutism
Effects of estrogen on CVS system
Vasodilation
- ↑ NO production w/i minutes
- ↑ inducible NOS and PGI2
Retention of water and salt
- ↓ Osmotic threshold for release of ADH
↑ Plasma level of angiotensinogen
- Stimulatory on liver
↑ Serum triglycerides and ↓ total serum cholesterol
- ↑ HDL, ↓ LDL => ↓ Atherosclerosis
↑ Coagulability of blood
- ↑ Fibrinogen and blood clotting factors (VII to X) and inhibit antithrombin III formation
=> ↑ Venous thromboembolism
Severe adverse effects of oral combined contraceptives
- Venous thromboembolism
- Myocardial infarction
- Hepatic adenoma and HCC
- Breast Ca
- Cervical Ca
Venous thromboembolism of oral combined contraceptives
- Estrogen dose
- ↓ Risk with 2nd gen. pills
- Debatable ↑ risk with 3rd gen. pills
- Changes in platelet functions and fibrinolytic system
- ↓ Venous blood flow
- Endothelial proliferation in veins and arteries
- ↑ Coagulability of blood => ↑ Incidence of thrombosis
Myocardial infarction of oral combined contraceptives
Risk factors:
- Sedentary, obese
- Hx of preeclampsia, HT, DM, hyperchloesteremia
- Smokers
- > 35 y/o
- Thrombotic mechanism
- Lower incidence with stroke
Carcinogenic effects of oral combined contraceptives
Hepatic adenoma and HCC
- rare and debatable
Breast Ca
- No significant increase in population
- ↑ Risk in younger women
Cervical Ca
- Debatable
Contraindication of oral combined contraceptives
- Liver diseases or tumours
- Hx of ischemic heart disease or stroke
- Blood clotting disorders
- Smoker aged > 35
- Ca breast or genital tract
- DM
- Headache (migraine)
- High BP (> 180/110)
- Major surgery
DDI of oral combined contraceptives
Enzyme inducers
- ↓ Effectiveness by ↑ estrogen metabolism by CYP450
e. g. Rifampicin, Barbiturates, Anticonvulsants
Antibiotics
- ↓ Effectiveness by ↓enterohepatic recirculation of steroid hormones through disturbance of bacterial flora of gut
e. g. Ampicillin, Tetracycline
Transdermal combined contraceptives
Ortho Evra
- 150 μg Norelgestromin, 20 μg Ethinylestradiol daily to systemic circulation
- Bypasses GI tracts
- Application-site reactions, breast discomfort, dysmenorrhea
Background of progestogen-only contraceptives
- Estrogens are contraindicated or undesirable
- NO CVS side effects of combined pill
MAO
- Thickening of cervical mucus => ↓ sperm penetration
- Endometrial alterations => impair implantation
- Slow freq. of GnRH pulse and blunt LH surge
Contraindication
- Undiagnosed vaginal bleeding, liver diseases, Ca breast
Drugs of progestogen-only contraceptives
Minipill
- 350 μg Noethisterone or 75 μg Norgestrel
- Short safety interval: same time every day w/o interruption
- Missed if 3 hrs late => Extra precautions for up to 7 days
- Side effects: erratic uterine bleeding, ectopic pregnancy
150 mg Medroxyprogesteone acetate (IM)
- Effective for 3 months
- ↑ LDL/HDL ratio, ↓ bone density
30 mg Levonogestrel or 68 mg Etonogestrel (implant)
- Subdermal slow-release implant, removable any time
- Local irritation, headache, weight gain, mood changes
Emergency postcoital contraceptive
- Short course of high dose oral contraceptive
- Preven: 2X [50 μg Ethinylestradiol, 250 μg Levonorgestrel]
- Plan B: 750 μg Levonorgestrel
- 1st dose taken w/i 72 h, 2nd dose 12 h later
- ↓ Fallopian tube motility, direct effect on endometrium
- Side effects: nausea, vomiting
Non contraceptive therapeutic uses of female sex steroids
Menstrual problems
- Premenstrual Syndrome (PMS)
- Dysmenorrhoea
- Menorrhagia
- Signs and symptoms relieved by obliteration of menstrual cycle with combined oral contraceptives
Replacement therapy
- Young patients
- Estrogen deficiency ∵ hypogonadism, hypopituitarism
- Conjugated estrogens or ethinylestradial at 11-13 y/o => induce puberty
- Patients > 50 y/o
- Loss of ovarian follicular activity
- Permanent cessation of menstruation
- ↓ Estrogen levels => hot flashes, vaginal atrophy, osteoporosis, CVS diseases
- Menopausal hormonal therapy with estrogens alone or with medroxyprogesterone
Specific estrogen receptor modulators (SERM)
- Differentially altering conformation of ER in diff. tissues
- Tissue specific estrogenic activities
- Beneficial actions (bone, brain, liver during HRT)
- No activity or antagonist activity in tissues where estrogenic actions might be deleterious (e.g. breast and endometrium)
Drugs of SERM
Tamoxifen, Toremifene
- Antiestrogenic: mammary tissue
- Estrogenic: plasma lipids, endometrium, bone
- Palliative treatment of estrogen dependent Ca breast
- Orally active, t1/2 = 7-14h
- 10-20mg twice daily
- Nausea, vomiting, hot flashed
- Proliferation of endometrial cells => Risk of endometrial Cancer
Reloxifene
- Antiestrogenic: breast
- Estrogenic: plasma lipids, bone
- No action: endometrium
- Prevention of postmenopausal osteoporosis
- Ant-proliferation of ER +ve. Ca breast
- Orally active, high first-pass effect
- Large volume of distribution, t1/2 > 24h
- Hot flashes, leg cramps, risk of deep vein thrombosis
Antiestrogens
Clomiphene
- Partial agonist of estrogen receptors
=> Fails to promote full estrogenic activity after binding
- Impairs recycling or synthesis of estrogen receptors
=> Estrogen insensitivity, antagonism
- Blocks inhibitory action of estrogen on LH, FSH release from ant. pituitary
=> More GnRH per pulse
=> ↑ LH, FSH
=> Induce ovulation (treatment of infertility due to lack of ovulation)
- Well absorbed orally, t1/2 = 5-7d (plasma protein binding, enterohepatic cycling, accumulation in fat)
- MAO relies on integrity of hypothalamic-pituitary-ovarian axis
- 50mg orally, daily for 5 days, starting on 1st day of menstruation
- Hot flashes, ovarian enlargement, multiple births
Antiprogestogen
Mifepristone (RU486)
- 19-Nor progestin norethisterone derivative
- Partial agonist at P4 receptors
- Inhibits glucocorticoid and androgen receptors
- Terminate early pregnancy (< 49 days)
- Sensitise uterus to contractile action of PG
- Orally active, long plasma t1/2 (20-40h)
- Single oral dose (600mg) followed 48h later by intravaginal pessary of Gemeprost or oral Misoprostol
- Postcoital contraceptive => prevent implanation
- Vomiting, diarrhea, pain, vaginal bleeding
