This document discusses sex hormones, including estrogens, progestogens, and their antagonists. It provides details on:
- Natural and synthetic estrogens and progestogens, their mechanisms of action, effects, clinical uses, and adverse effects.
- Inhibitors and antagonists of estrogens and progestogens like tamoxifen, clomiphene citrate, mifepristone, and danazol.
- Uses of hormones in contraception including combination oral contraceptives, progestin-only contraceptives, implants, IUDs, and emergency contraception.
- The document serves as a comprehensive review of these hormone classes and their applications in
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Sex Hormones and Their Antagonists: Estrogen, Progesterone, Tamoxifen, and More
1. SEX HORMONES
(ESTROGEN
PROGESTERONE AND
THEIR ANTAGONISTS)
BY
DR BAKUT JOHN MAIGANGA
DEPARTMENT OF CLINICAL PHARMACOLOGY AND THERAPEUTICS
FACULTY OF BASIC CLINICAL SCIENCES
ABUTH, ZARIA.
2. INTRODUCTION
• The ovaries are stimulated by gonadotropins (FSH/LH) for gametogenic and
endocrine function
• The hormones produced by the ovaries are estrogen, progesterone, inhibin and
activin
• Disturbances in ovarian function can lead to menstrual abnormalities, mental and
emotional stress
3. NATURAL ESTROGENS
• Natural estrogens are steriodal
• Major estrogens produced by the ovary are estradiol (E2), estrone (E1) and estriol (E3)
• Estradiol is mainly produced by Theca granulosa
• Estrone and Estradiol are formed in the liver, ovary and peripheral tissues from
androstenedione and other endogenous steriods
4. SYNTHETIC ESTROGENS
• Produced from chemical alteration of natural estrogen
• Synthetic forms have increased oral effectiveness and therapeutic use
• Common examples in
Steriodal Synthetic Agents
Ethinyl estradiol, Mestranol, Quinestrol
Non Steroidal Synthetic
Diethylstilbesterol, Chlorotrianisene, Methallenestril, Dienestrol, Benzestrol,
Hexestrol, Methestrol
5. SYNTHETIC ESTROGENS
• Mechanism of Action; Binds to Estrogen receptors to form receptor-hormone complex
that bind to specific sequence of nucleotide referred to as Estrogen response elements.
They promote various genes and regulate their transcription
• Pharmacokinetic;
When in circulation, it binds strongly to α2 globulin (Sex binding globulin [SHBG])
Has low affinity for albumin
Estradiol is converted to estrone and estradiol in the liver
Excreted in bile as conjugated metabolites
Their conjugated metabolites may be hydrolysed in the intestine to active reabsorbable
compounds
6. EFFECTS OF ESTROGEN ACTIVITY
1. Stimulates Female maturation; Breast and genital development
2. Endometrial growth and development
3. Decreases the rate of resorption of bones by promoting apoptosis of osteoclast
and antagonizing osteoclastogenic and pro-osteoclastic effects of parathyroid
hormone and IL-6
4. Alteration in composition of plasma lipid causes estrgens to increase HDL
7. EFFECTS OF ESTROGEN ACTIVITY
5. Increases the production of thyroid binding globulin, SHBG, transferitin, renin and
fibrinogen
6. Enhances coagulation of serum by increasing factor II, VII, IX, X
7. Maintenance and increase in libido
8. CLINICAL USES
A. Primary hypogonadism; due to failure of ovarian development, premature menopause,
castration or menopause
• Estrogen is given from 11-13 years to stimulate growth and prevent osteoporosis
• In delayed puberty it is use to initiate pubertal development
• About 5-10 mcg ethinyl estradiol on day 1-21 of each month, progesterone is added after
the first uterine bleed
9. CLINICAL USES
B. Post menopausal hormone therapy;
• Given to relieve symptoms of menopause and bone demineralization
• Given from day 21-25 of each month
• Ethinyl estradiol 0.01-0.02 mg/day
• Conjugated estrogen 0.3-1.25 mg/day
C. Suppression of ovulation in intractable dysmenorrhea
10. ADVERSE EFFECTS
• Uterine bleeding
• Cancer (Breast, Endometrial, Adenocarcinoma of vagina)
• Breast tenderness
• Migraine
• Cholestasis
• Gallbladder disease
• Hypertension
12. PROGESTINS
A. Natural Progesterone
• Produced in the ovary, testes, placenta and adrenal cortex from circulating cholesterol
• In the ovary it is produced in the corpus luteum
• Male plasma level is about 0.03 mcg/dl
• Female plasma level, 0.5 – 2 mcg/dl and higher in pregnancy
• Other examples; Hydroxyprogesterone, Medroxyprogesterone acetate, Megestetrol
acetate
13. PROGESTINS
B. Synthetic Progestin
• These are “ 19-nor, 13-ethyl ” steroid compound
1. 17-ethinyl testosterone derivatives; Dimethisterone
2. 19-Nortesterone derivatives; Desogestrel, Norethynodrel, Lynestrenol, Norethindrone
acetate, Norgestrel
14. B. SYNTHETIC PROGESTIN
• Mechanism of Action; Binds to progesterone receptors in the cytoplasm and nucleus to
form progesterone – receptor complex which leads to the formation of progesterone
response element and activates gene transcription
• Pharmacokinetics
Rapidly absorbed irrespective of the route of administration
Plasma half life of 5 minutes
Stored temporarily in body fat
Metabolized in the liver, converted to pregnanediol and conjugated with glucuronic acid
Excreted in urine as pregnanediol glucuronide
15. EFFECT
• Stimulates lipoprotein lipase activity to favor fat deposition
• Increases basal insulin level to increase glucose production
• It increases glycogen storage in the liver
• Promote ketogenesis
• Increases body temperature
• Responsible for Alveolo-tubular development of the secretory apparatus in the breast
16. CLINICAL USES
1. Therapeutic application;
Hormone replacement therapy
Hormonal contraception
Long term ovarian suppression
Treatment of dysmenorrhea, Endometriosis, Bleeding disorder
2. Diagnostic application
Progesterone challenge test in patients with amenorrhea
17. INHIBITORS OF ESTROGEN AND PROGESTERONE
A. Tamoxifen;
A non-steroidal competitive partial agonist of Estradiol at the Estrogen receptors
It is a selective Estrogen receptor modulator (SERM)
Use for palliative treatment of breast cancer(Decreases contralateral Breast Ca by 35%,
no further improvement after 5 years of treatment)
Approved for chemoprevention of breast cancer in high risk individuals
Half life of 7 – 14 hours
Excreted by liver
Given orally 10 - 20 mg twice daily
19. B. CLOMIPHENE CITRATE
• A Partial Estrogen Agonist
• It competitively binds to Estrogen receptors with greater affinity than endogenous estrogens
• Half life, 5 – 7 days
• Effect
It has the ability to stimulate ovulation in women with Oligomenorrhea, Amenorrhea and
ovulatory dysfunction.
In PCOS, it is believed to block the feedback inhibitory influence of Oestrogen on the
hypothalamus, causing a surge of gonadotropins which leads to ovulation
20. B. CLOMIPHENE CITRATE
• Adverse Effects
Hot flushes, headaches, constipation, allergic skin reaction, reversible hair loss,
depression, fatigue, soreness of breast, weight form, urinary frequency, heavy menses
• Cautions
Use with caution in individuals with enlarged ovaries.
Treatment greater than 1 years is associated with low grade Ovarian ca.
It may cause visual symptoms hence the need to avoid driving
21. MIFEPRISTONE
• Is a 19 non steroid that binds strongly to progesterone receptor and inhibits its activity.
• It has luteolytic properties in 80% of women
• It is used as an emergency contraceptive due to that property
• Single dose of 600mg is used for post coital contraceptive.
• May be used in treatment of Endometrial hyperplasia, Cushing’s syndrome, Breast ca,
Meningiomas that contain glucocorticoids and progesterone receptors.
• For termination of pregnancy when combined with prostaglandin E1 (95%) success rate.
• Adverse effects vomiting, nausea,
22. DANAZOL
• Is an isoxazole derivative of Ethisterone ( 17 & ethinyltestoterone ) with weak progestational,
androgenic & glucocorticoid activities
• It is used to suppress ovarian function; inhibits mid-luteal surge of FSH, LH
• Binds to androgen, progesterone, and glucocorticoid receptors and can translocate the androgen-
receptor into the nucleus to initiate androgen specific RNA synthesis.
• It does not bind to intracellular oestrogen receptors but binds to sex-hormone binding globulin
• It inhibits (3β,17 α ) hydroxysteroid dehydrogenase, (17α, 11β, 21β) hydroxylase, P450
• Does not inhibit aromatase
23. • Half life of 15 hours
• Highly concentrated in liver, adrenals and kidneys
• Excreated in urine and feaces
• Ethisterone, a major metabolite of Danazol has both progestational and mild
androgenic effect
• Uses; treatment of endometriosis, fibrocystic disease of breast, heamatologic and
allergic disorder
• Side effects; weight gain, oily skin, acne, increased hair growth, deepening of
voice, hot flushes
• Contraindication; hepatic dysfunction, pregnancy, breast feeding
24. • ANASTROZOLE
Selective non-steriodal inhibitor of aromatase enzyme required for estrogen
synthesis.
Effective in women with resistant breast tumour to tamoxifen
• LETROZOLE is similar to Anastrazole
• FEDROZOLE is an oral nonsteroidal inhibitor of aromatase activity
• FULVESTRANT
• Pure estrogenic receptor antagonist somewhat more effective than partial
inhibitors, use in management of breast ca
25. HORMONAL CONTRACEPTION
• Large number of oral Contraceptives containing Oestrogens or Progestins or both are
available for use in clinical practice
COMMON FORMS
• Combination of Oestrogens and Progestins
• Continues Progestin therapy without Oestrogens
• Monophasic form; constant usage of both components during the cycle.
• Biphasic / Triphasic ( dosage of one or both components is changed once or twice during
the cycle)
MECHANISM OF ACTION
• Combination of Oestrogen / Progesterone exerts their contraceptive effects largely through
selective inhibition of pituitary function that results in inhibition of ovulation
26. HORMONAL CONTRACEPTION
Pharmacological Effects
Ovary; Depresses follicular development, return to ovulation is upto 75% in first
posttreatment cycle, 97% by the third
Uterus; Thicken cervical mucous, endometrial glandular atrophy
Breast; Enlargement, suppresses lactation,
CNS; Oestrogen is excitatory, Progesterone is thermogenic
Blood; increases the production of factors VII, VIII, IX, X, decreases antithrombin
III
27. CLINICAL USES
• Contraception; COCPs are effective, pregnancy rate while on it, is 0.5 – 1 per 100
women years. Higher; if more than one missed dose, use of enzyme inducers
• Treatment of endometriosis, Dysmenorrhea
Side effects;
• Nausea, vomiting, Headaches, Withdrawal bleeds, weight gain, inceased skin
pigmentation, Acne, Hirsutism, Amenorrhea,
Adverse Effect;
• Venous Thromboembolic Disease (1 per 1000 women year), Myocardial infarction (4
– 185 per 100000 users), Cerebrovascular disease (37 per 100000 user of high
doses), Depression (6% of clients), ??? Cervical cancer, ??? Early manifestation of
breast cancers
28. PROGESTINS
• Oral; POCP
• Injectible; Noristerat (200mg of Norethisterone, once 2 Monthly), Depot
Medroxyprogesterone (150 mg, once 3 Monthly)
• Implant/ subdermal; Etonogestrel 68mg (Implanon/ Nexplanon), Levenogestrel 75
mg x 2 rods (Jadelle),
• Intrauterine contraceptive system; LNG IUS (Mirena)
29. POST COITAL CONTRACEPTIVES
• Pregnancy can be prevented following coitus by administration of Oestrogens,
progestins, or in combination
• “Morning after pills”
• When treatment is commenced within 72 hours of coitus, it is 99% effective
• Examples;
1. Levenogestrel 0.75 mg 12 Hourly for 24 hours
2. Norgestrel 0.5mg + Ethinyl estradiol 0.05 mg (Ovral, Preven)
3. Mifeprestone 600mg + Misoprostol 400mcg stat
4. Conjugated Oestrogen 10mg tids x 5 days
5. Ethinyl Oestradiol 2.5 mg bid x 5 days
30. REFERENCES
1. Bertram G K, Masters S B, Trevor J A, Basic and clinical Pharmacology twelfth
Edition 2012; Pg 659-681.
2. Charles C, Robert E, Modern pharmacology with clinical applications