HUF 2-34&35 Pharmacology of reproductive hormones

Question 1

Estrogens

Answer 1

• Principal source: ovaries
• Estradiol by granulosa cells
• Converted to estrone and estriol in liver
• Placenta: estrone, estriol
• Adipose tissue: estrone
• Estradiol > estrone > estriol

Question 2

Synthetic estrogens

Answer 2

• Steriodal: Menstranol, Ethinylestradiol
• Non-steroidal: Diethystilbestrol, Chlorotrianisene
• Inhibit first-pass hepatic metabolism
  => ↑ oral potency

Question 3

Mechanism of action of estrogens

Answer 3

• 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

Question 4

PK of natural estrogens

Answer 4

• 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

Question 5

PK of Ethinylestradiol

Answer 5

• 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

Question 6

Progestogen

Answer 6

• 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

Question 7

Mechanism of action of progestogens

Answer 7

• 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

Question 8

P4 derivatives

Answer 8

• 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

Question 9

Testosterone derivatives

Answer 9

• 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

Question 10

Combined oral contraceptive

Answer 10

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

Question 11

Hypothalamus-pituitary axis

Answer 11

• 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

Question 12

Effects of combined oral contraceptives on female reproductive tract

Answer 12

• ↓ 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)

Question 13

Benefits of combined oral contraceptives

Answer 13

• 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

Question 14

Minor unwanted effects of combined oral contraceptive-

Answer 14

• Mood changes: depression, loss of libido
• Nausea, vomiting, dizziness
• Breast fullness, tenderness (mastalgia)
• Amenorrhea, bleeding / spotting
• High BP
• Acne, weight gain, hirsutism

Question 15

Effects of estrogen on CVS system

Answer 15

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

Question 16

Severe adverse effects of oral combined contraceptives

Answer 16

• Venous thromboembolism
• Myocardial infarction
• Hepatic adenoma and HCC
• Breast Ca
• Cervical Ca

Question 17

Venous thromboembolism of oral combined contraceptives

Answer 17

• 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

Question 18

Myocardial infarction of oral combined contraceptives

Answer 18

Risk factors:

• Sedentary, obese
• Hx of preeclampsia, HT, DM, hyperchloesteremia
• Smokers
• > 35 y/o
• Thrombotic mechanism
• Lower incidence with stroke

Question 19

Carcinogenic effects of oral combined contraceptives

Answer 19

Hepatic adenoma and HCC
- rare and debatable

Breast Ca

• No significant increase in population
• ↑ Risk in younger women

Cervical Ca
- Debatable

Question 20

Contraindication of oral combined contraceptives

Answer 20

• 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

Question 21

DDI of oral combined contraceptives

Answer 21

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

Question 22

Transdermal combined contraceptives

Answer 22

Ortho Evra

• 150 μg Norelgestromin, 20 μg Ethinylestradiol daily to systemic circulation
• Bypasses GI tracts
• Application-site reactions, breast discomfort, dysmenorrhea

Question 23

Background of progestogen-only contraceptives

Answer 23

• 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

Question 24

Drugs of progestogen-only contraceptives

Answer 24

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

Question 25

Emergency postcoital contraceptive

Answer 25

- 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

Question 26

Non contraceptive therapeutic uses of female sex steroids

Answer 26

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

Question 27

Specific estrogen receptor modulators (SERM)

Answer 27

- 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)

Question 28

Drugs of SERM

Answer 28

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

Question 29

Antiestrogens

Answer 29

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

Question 30

Antiprogestogen

Answer 30

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