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Human Function II > HUF 2-34&35 Pharmacology of reproductive hormones > Flashcards

HUF 2-34&35 Pharmacology of reproductive hormones Flashcards

1
Q

Estrogens

A
  • Principal source: ovaries
  • Estradiol by granulosa cells
  • Converted to estrone and estriol in liver
  • Placenta: estrone, estriol
  • Adipose tissue: estrone
  • Estradiol > estrone > estriol
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2
Q

Synthetic estrogens

A
  • Steriodal: Menstranol, Ethinylestradiol
  • Non-steroidal: Diethystilbestrol, Chlorotrianisene
  • Inhibit first-pass hepatic metabolism
    => ↑ oral potency
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3
Q

Mechanism of action of estrogens

A
  • 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
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4
Q

PK of natural estrogens

A
  • 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
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5
Q

PK of Ethinylestradiol

A
  • 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
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6
Q

Progestogen

A
  • 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
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7
Q

Mechanism of action of progestogens

A
  • 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
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8
Q

P4 derivatives

A
  • 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
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9
Q

Testosterone derivatives

A
  • 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
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10
Q

Combined oral contraceptive

A

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
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11
Q

Hypothalamus-pituitary axis

A
  • 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
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12
Q

Effects of combined oral contraceptives on female reproductive tract

A
  • ↓ 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)
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13
Q

Benefits of combined oral contraceptives

A
  • 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
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14
Q

Minor unwanted effects of combined oral contraceptive-

A
  • Mood changes: depression, loss of libido
  • Nausea, vomiting, dizziness
  • Breast fullness, tenderness (mastalgia)
  • Amenorrhea, bleeding / spotting
  • High BP
  • Acne, weight gain, hirsutism
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15
Q

Effects of estrogen on CVS system

A

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

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16
Q

Severe adverse effects of oral combined contraceptives

A
  • Venous thromboembolism
  • Myocardial infarction
  • Hepatic adenoma and HCC
  • Breast Ca
  • Cervical Ca
17
Q

Venous thromboembolism of oral combined contraceptives

A
  • 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
18
Q

Myocardial infarction of oral combined contraceptives

A

Risk factors:

  • Sedentary, obese
  • Hx of preeclampsia, HT, DM, hyperchloesteremia
  • Smokers
  • > 35 y/o
  • Thrombotic mechanism
  • Lower incidence with stroke
19
Q

Carcinogenic effects of oral combined contraceptives

A

Hepatic adenoma and HCC
- rare and debatable

Breast Ca

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

Cervical Ca
- Debatable

20
Q

Contraindication of oral combined contraceptives

A
  • 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
21
Q

DDI of oral combined contraceptives

A

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
22
Q

Transdermal combined contraceptives

A

Ortho Evra

  • 150 μg Norelgestromin, 20 μg Ethinylestradiol daily to systemic circulation
  • Bypasses GI tracts
  • Application-site reactions, breast discomfort, dysmenorrhea
23
Q

Background of progestogen-only contraceptives

A
  • 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

24
Q

Drugs of progestogen-only contraceptives

A

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
25
Q

Emergency postcoital contraceptive

A
  • 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
26
Q

Non contraceptive therapeutic uses of female sex steroids

A

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
27
Q

Specific estrogen receptor modulators (SERM)

A
  • 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)
28
Q

Drugs of SERM

A

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
29
Q

Antiestrogens

A

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

30
Q

Antiprogestogen

A

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

Human Function II (35 decks)

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