الاسم : سعد بن محمد نور بن محمد ولي الرقم الجامعي : التخصص : معيد بكلية الصيدلة قسم الأدوية Pharmacology استخدام الحاسب لتقديم محاضرة في موضوع مختص بالبوربوينت

Umm Al-Qura University Faculty Of Pharmacy Medicinal Chemistry Department

Female Sex Hormones

Necessary for reproduction & development of secondary sex characters All hormones are biosynthesized in both sex but in female [estrogen & progesterone produced in large amounts] & in male [testosterone] After ovulation there are two probabilities 1.No pregnancy (no fertilization) → decline of hormones & menses 2.Pregnancy (fertilization) → ovary stop releasing hormones but corpus luteum & placenta start their hormonal secretion Female sex hormones Sex hormones

1.Development of ♀ primary sex characters (ovary, uterus & vagina) 2.Development of ♀ secondary sex characters (breast, soft of skin & voice) 3.Induction of uterus 4.Activation of Ca precipitation in bones 5.Prevention of anginal attack? ( mobilize circulating fats from blood to fat depot ) In female by ovary, adrenal cortex & placenta (pregnancy) In male (small amounts produced by testes & adrenal cortex) Physiological role: Estrogen Female sex hormone produced by:

Synthesis of estrogen:

EstradiolEstrone The most potent estrogen (develop sex characters). Principal female sex hormone, produced in the ovary. Responsible for secondary female sex characteristics. Very weak oral activity?? 1- Degradation of ring D by bacterial flora in GIT 2- 1 st pass effect (oxidation of 17-OH, conjugation) Taken by injection as ester?? it is orally inactive, ester preparation prolong the action of drug The major estrogen in blood Orally active No 17-OH N.B It is less active than Esradiol but more active than its metabolite Estriol EstriolEquillin The most abundant & weakest estrogen Orally active ?? 17-OH is protected (sandwiched between 16α-OH & 18β-methyl Present in mares

Semi-synthetic estrogen Ethinyl estradiolMestranol Assay: dissolve in NaOH (less than stoichiometric amount, add known excess of standard AgNO 3 & the ppt is filtered & liberated HNO 3 is titrated against standard NaOH, E.P. potentiometrically Prodrug Metabolized rapidly by O- demethylation to ethinyl estradiol following oral administration ? Used as oral contraceptive (orally active): due to presence of 17α-ethinyl gp which prevent oxidation (metabolism) to estrone.

Synthesis Metabolism of ethinyl estradiol

Conjugated water soluble metabolite (exist as ionized salts) Conjugated estrogen (equine estrogens) They are used as replacement therapy in menopause?? Because they have short duration & weak activity (attenuated), so can be used safely (avoid tumors) used alone or with progesterone Na equillin (∆ 7 estrone) sulfate Sodium 17-oxo-estra-1,3,5(10),7-tetraen-sulfate

1.Contraceptive (with progestins) 2.Replacement therapy (menopause) 3.↓ severity of osteoporosis: (bone thinning) + exercise + nutrition 4.In ttt of endometriosis, androgen dependant prostate cancer, breast cancer in menopause. 1.Can stimulate breast cancer in certain premenopausal women, risk ↑ with long term estrogen therapy 2.Non-cancer side effects: migraine, gallstone & nausea? 3.? Why its better to use contraceptive containing estrogen + progestins rather than estrogen alone (Progestins prevent or ↓ the risk for cancer formation) Pharmcological uses of estrogen: Side effects:

Non-steroidal estrogen: trans form has 10 times the activity of cis form?? Because trans isomer resemble more closely estradiol ? No longer used as replacement therapy in menopause Due to high incidence of uterine cancers in women Fosfestrol: Phosphate gp act as targetor for cancer cells  DES & Fosfestrol: used in ttt of prostatic cancer DES: have estrogenic activity as estrogen Uses:

Similar to DES but the two C 2 H 5 gps replaced by two ethylidene gps Uses: Intravaginally for vaginal & urethral atrophy Dienestrol:

1.As fertility drugs: Estradiol inhibit secretion of gonadotrophic hormone (LH & FSH) by feed back inhibition. Estrogen antagonist allow release of LH & FSH which stimulate ovulation 2. Antitumor: in estrogen dependant breast cancer Estrogen antagonist Uses: (two purpose)

Assay: Non aqueous titration (why) Because it has embedded estrogenic activity so it ↑HDL & ↓ LDL→ prophylaxis of angina & ↑ Ca deposition in bone

 Inhibit Aromatase enzyme so block conversion of androgen → estrogen  They can so affect reproduction functions Conversion of androgen to estrogen Aromatase inhibitors 1.Treatment of estrogen dependant cancers (e.g. breast cancer) 2.Second line treatment after Tamoxifen Uses:

Aminoglutethimide  Not selective, reversible Competitive inhibitor  Aniline N interact with heme iron atom in Aromatase enzyme preventing binding to steroidal substrate

Progestins

Secreted by: Corpus luteum (ruptured follicles in ovary) & placenta (in pregnancy) Progestins 1.Inhibit uterus contraction (maintain pregnancy) 2.Prevent ovulation (during pregnancy) 3.Produce viscous cervical mucous (estrogen produces liquefied alkaline mucous) 4.Excess progesterone → feed back inhibition of LH (contraception) Physiological role

Therapeutic uses of progestins 1.Contraceptive (with or with out estrogen) 2.Prophylaxis & treatment of endometrial cancer (postmenopausal) 3.Habitual abortion & uterine bleeding Pregnant derivatives Dydrogesterone (Duphastone ®) 1.Improved oral activity & chemical stability 2.Lack of estrogenic, androgenic & mineralocorticoids properties Uses: to maintain pregnancy does not inhibit ovulation (i.e no contraception) These changes in chemical structure causes

It is more active & longer duration > progesterone ???? Due to 17α-ester which hinder reduction of 20-one gp 17α-hydroxyprogesteron hexanoate (caproate) Protection of ring D

Protection of ring D with changes in ring B Medroxyprogesterone acetate Highly active orally ????? Due to Depo-Provera: IM contraceptive for prolonged period (3-6monthes) 1.C 6 methyl gp → hinders 6- hydroxylation 2.17α-ester → hinders reduction of 20-one gp Mechanism: increase viscosity of vaginal fluid → difficult in movement of sperms to fertile ovum

Combined type Estrogen + progesterone oralEthinyl estradiol + Progestin Inject.Ester & long duration estrogen Progestin only typeprogesteroneInject.Depo-provera® Implants Impregnated by levonorgestrel butanoate (up to 5 years) Intra-uterine deviceCauses widening of cervix → death of fertilized ovum  Estrogens: inhibit LH & FSH (negative feed back mechanism)  Progestins: ↑ viscosity of vaginal fluid, hinder sperms movement & fertilization Contraceptive agents Mechanism:

o Presented by: Saad Noor Wali