Estrogens & Estrogens & AntiestrogensAntiestrogens

Menstrual cycleMenstrual cycle... Changes and ... Changes and hormonal eventshormonal events

Natural estrogens:Natural estrogens: Estadiol >> Estrone > EstriolEstadiol >> Estrone > EstriolIneffective orallyIneffective orally Synthesis:Synthesis:From cholesterol ; role of aromatase From cholesterol ; role of aromatase

enzyme in converting androgens enzyme in converting androgens (testosterone & androsteindione) to (testosterone & androsteindione) to estrogenestrogen

Estrogen synthesis:Estrogen synthesis:From cholesterolFrom cholesterol DEDE DehDeh

Cholesterol Pregnenolone Cholesterol Pregnenolone ProgesteroneProgesterone

HydHyd

Testosterone Androstenedione Testosterone Androstenedione Hydroxyprog.Hydroxyprog.

AromataseAromatase

Estradiol EstroneEstradiol Estrone

Transport:Transport: SHBG SHBG M.O.A:M.O.A:

Estrogen receptors (ER-Estrogen receptors (ER-αα; ER-; ER-ββ))

Modulation of gene transcription Modulation of gene transcription (nuclear receptors)(nuclear receptors)

Stimulation of endometrial nitric oxideStimulation of endometrial nitric oxide

synthase nitric oxide synthase nitric oxide vasodilatation vasodilatation

cardioprotectioncardioprotection

Estrogen actions:Estrogen actions:- 11◦◦ & 2 & 2◦◦ sexual characteristics of females sexual characteristics of females- Proliferation of the endometrium & Proliferation of the endometrium &

follicular maturationfollicular maturation- ↑ ↑ elasticity of skinelasticity of skin- ↑ ↑ synthesis of certain globulins by the synthesis of certain globulins by the

liverliver

( SHBG, corticosteroid binding globulin ( SHBG, corticosteroid binding globulin & thyroid binding globulin)& thyroid binding globulin)

Cont. estrogen actions:Cont. estrogen actions:- ↑ ↑ synthesis of certain clotting factors synthesis of certain clotting factors

(fibrinogen, factors VII; IX & X) and ↓ (fibrinogen, factors VII; IX & X) and ↓ activity of antithrombin IIIactivity of antithrombin III

- ↓ ↓ cholesterol, ↑ HDL & ↓ LDL blood cholesterol, ↑ HDL & ↓ LDL blood levels levels

- Salt & water retentionSalt & water retention Absorption & metabolism of estrogens:Absorption & metabolism of estrogens:

Conjugation → enterohepatic circulationConjugation → enterohepatic circulation

Estrogens clinical uses:Estrogens clinical uses:- HRTHRTPostmenopausal syndrome & osteoporosis, Postmenopausal syndrome & osteoporosis,

prevention of heart attacksprevention of heart attacks- Components of OCPComponents of OCP’’ss- Prostate, breast, endometrial cancer + Prostate, breast, endometrial cancer +

progesteroneprogesterone- DysmenorrheaDysmenorrhea- InfertilityInfertility- Acne, hirsutismAcne, hirsutism

Estrogen preparations:Estrogen preparations:- Synthetic steroidalSynthetic steroidalEstradiol benzoate; Estradiol Estradiol benzoate; Estradiol

valaratevalarateEthinylestradiol; Mestranol... Ethinylestradiol; Mestranol... - Synthetic non steroidal estrogensSynthetic non steroidal estrogensDiethylstilbesterolDiethylstilbesterol- Conjugated estrogensConjugated estrogensEstrone sulfonate Estrone sulfonate

Estrogen side effects:Estrogen side effects:- Nausea & vomitingNausea & vomiting- Headache, migrainous headacheHeadache, migrainous headache- Dizziness, weight gainDizziness, weight gain- Salt & water retention → ↑ BPSalt & water retention → ↑ BP- ↑ ↑ risk of thromboembolism and risk of thromboembolism and

endometrial cancerendometrial cancer- Teratogenic effectTeratogenic effect

Antiestrogens:Antiestrogens:

** Competitive antagonists at estrogen ** Competitive antagonists at estrogen receptors:receptors:

Tamoxifen & clomiphene citrateTamoxifen & clomiphene citrate

Tamoxifen is considered an estrogen agonist Tamoxifen is considered an estrogen agonist on bone and endometrium; long term use of on bone and endometrium; long term use of tamoxifen could lead to endometrial cancertamoxifen could lead to endometrial cancer

Tamoxifen acts also as an estrogen agonist in Tamoxifen acts also as an estrogen agonist in breast; so used in certain cases of breast breast; so used in certain cases of breast cancercancer

Clomiphene citrate and tamoxifen Clomiphene citrate and tamoxifen act as estrogen antagonists at act as estrogen antagonists at the level of the hypothalamus, so the level of the hypothalamus, so mainly used to manage infertility mainly used to manage infertility in ♂’s and ♀’s in ♂’s and ♀’s

Clomiphene citrate and tamoxifen Clomiphene citrate and tamoxifen are given orallyare given orally

Selective estrogen receptor Selective estrogen receptor modulators (SERMmodulators (SERM’’s):s):

Nonhormonal pharmacological Nonhormonal pharmacological agents that bind estrogen agents that bind estrogen receptors producing agonistic receptors producing agonistic activity in certain tissues (in activity in certain tissues (in bone) and estrogen antagonistic bone) and estrogen antagonistic effect at other tissues (breast effect at other tissues (breast and endometrium)and endometrium)

RaloxifeneRaloxifeneOrally effective SERM widely used in the Orally effective SERM widely used in the

management of osteoporosis (prophylactic management of osteoporosis (prophylactic and Rand Rxx))

Recently some researchers consider Recently some researchers consider tamoxifen and clomiphene citrate as SERMtamoxifen and clomiphene citrate as SERM

****Aromatase inhibitors:Aromatase inhibitors:Nonselective: AminoglutithemideNonselective: AminoglutithemideSelective: Anastrazole; FadrozoleSelective: Anastrazole; FadrozoleMainly used in the management of breast Mainly used in the management of breast

cancercancer

ProgesteroneProgesterone

Biosynthesis:Biosynthesis:

From cholesterolFrom cholesterol DEDE DehDeh

Cholesterol Cholesterol Pregnenolone Pregnenolone ProgesteroneProgesterone

Feedback effectsFeedback effects

Physiological & Pharmacological Physiological & Pharmacological effects:effects:

- Endometrial differentiation, growth Endometrial differentiation, growth and development. Sudden withdrawal and development. Sudden withdrawal → bleeding (menses) → bleeding (menses)

- Maintenance of pregnancyMaintenance of pregnancy- Breast developmentBreast development- Vagina: ↓ cornification, ↑ mucus Vagina: ↓ cornification, ↑ mucus

contentcontent- Cervix: ↑ viscosity ↓ NaCl contentCervix: ↑ viscosity ↓ NaCl content- Thermogenic effectThermogenic effect- Weak aldosterone-like effectWeak aldosterone-like effect

Absorption & metabolism:Absorption & metabolism:

Progesterone is available in oral; depo (I.M) Progesterone is available in oral; depo (I.M) injectable and subdermal implants dosage injectable and subdermal implants dosage formsforms

Preparations:Preparations:

Medroxyprogesterone; Norethindrone Medroxyprogesterone; Norethindrone acetate; Norethindrone; Norgestrel; acetate; Norethindrone; Norgestrel; Megesterol acetate; Hydroxyprogesterone Megesterol acetate; Hydroxyprogesterone caproate; Cyproterone acetate (Ca caproate; Cyproterone acetate (Ca prostate); Dydrogesterone (IVF)prostate); Dydrogesterone (IVF)

Progesterone clinical uses:Progesterone clinical uses:- Components of OCP’sComponents of OCP’s- Dysfunctional uterine bleedingDysfunctional uterine bleeding- Endometrial; breast; prostate cancerEndometrial; breast; prostate cancer- Abortion or maintaining pregnancyAbortion or maintaining pregnancy- Endometriosis Endometriosis Progesterone side effects:Progesterone side effects:Depression; weight gain; salt-water Depression; weight gain; salt-water

retentionretention

Antiprogestins:Antiprogestins:

MifepristoneMifepristone Clinical uses:Clinical uses:- Abortifacient + PGAbortifacient + PG- Induction of labor + PGInduction of labor + PG- Progesterone-dependent cancerProgesterone-dependent cancer- Cushing’s syndromeCushing’s syndrome

ContraceptionContraception

I. Male contraception:I. Male contraception:1. Behavioral1. Behavioral2. Mechanical (e.g. condoms) ± 2. Mechanical (e.g. condoms) ±

spermicidal agent (nonoxynol-9)spermicidal agent (nonoxynol-9)3. Drugs3. DrugsEstrogens; progestins; danazol; Estrogens; progestins; danazol;

GnRH agonists & antagonists; GnRH agonists & antagonists; spermicidal agents; gossypolspermicidal agents; gossypol

4. Surgical procedures e.g. 4. Surgical procedures e.g. vasectomyvasectomy

II. Female contraception:II. Female contraception:1. Behavioral1. Behavioral2. Mechanical2. MechanicalDiaphrams; condoms ± spermicidal Diaphrams; condoms ± spermicidal

agents;agents;IUD’s ± progestins (progestasert)IUD’s ± progestins (progestasert)3. Drugs3. Drugs- Estrogen alone- Estrogen aloneMorning after pill or postcoital pillMorning after pill or postcoital pillEthinylestradiol; DES; mestranol….. ×5Ethinylestradiol; DES; mestranol….. ×5

- Progesterone alone- Progesterone alone

The minipillThe minipill

* Norethisteron... Tab* Norethisteron... Tab

* I.M medroxyprogesterone* I.M medroxyprogesterone

Depo-provera (effect lasts in 3-6 Depo-provera (effect lasts in 3-6 months)months)

* Subdermal progesterone implants* Subdermal progesterone implants

Levonorgesrel (effect lasts in 5-6 Levonorgesrel (effect lasts in 5-6 years) years)

4. Sequential 4. Sequential

Estrogen followed by progesteroneEstrogen followed by progesterone

5. Combined oral contraceptive pills 5. Combined oral contraceptive pills (COCP’s)(COCP’s)

ethinylestradiol or mestranol + Norgestrelethinylestradiol or mestranol + Norgestrel

ethinylestradiol or mestranol + ethinylestradiol or mestranol + NorethisteroneNorethisterone

* Estrogen + progesterone in different * Estrogen + progesterone in different ratios (lowest E highest P to achieve the ratios (lowest E highest P to achieve the lowest or zero failure rate)lowest or zero failure rate)

MOA of OCP’s:MOA of OCP’s:

- Inhibition of ovulation (major Inhibition of ovulation (major mechanism)mechanism)

At the level of the pituitaryAt the level of the pituitary- ↑ ↑ viscosity of cervical mucusviscosity of cervical mucus- Change in Fallopian tube motilityChange in Fallopian tube motility

OCP’s side effects:OCP’s side effects:- Nausea, vomiting, dizziness, Nausea, vomiting, dizziness,

headache, migraine, nervousness, headache, migraine, nervousness, depressiondepression

- Salt & water retention → ↑ BPSalt & water retention → ↑ BP- Thromboembolic disease, embolism, Thromboembolic disease, embolism,

MIMI- Vaginal yeast growthVaginal yeast growth- Postpill amenorrhea and infertilityPostpill amenorrhea and infertility

OCP’s contraindications:OCP’s contraindications:- History of thromboembolic History of thromboembolic

diseasedisease- Severe headacheSevere headache- Severe nausea & vomitingSevere nausea & vomiting- Liver dysfunctionLiver dysfunction- PregnancyPregnancy- Abnormal menstrual cycles Abnormal menstrual cycles

OCP’s drug-drug interactions:OCP’s drug-drug interactions:- Drugs inhibiting enterohepatic Drugs inhibiting enterohepatic

circulationcirculationAmpicillin; cephalosporins; teracyclines; Ampicillin; cephalosporins; teracyclines;

sulfonamides; co-trimoxazolesulfonamides; co-trimoxazole- Drugs ↑ metabolismDrugs ↑ metabolismPhenobarbitone; phenytoin; Phenobarbitone; phenytoin;

ethosuximide; rifampicin; griseofulvin…ethosuximide; rifampicin; griseofulvin…- Miscellaneous interactionsMiscellaneous interactions+ anticoagulants →↓ activity of anticoag. + anticoagulants →↓ activity of anticoag.

+ insulin → ↑ insulin need+ insulin → ↑ insulin need