PRESENTED BY Nohad A AlOmari 16/2/2014 Organic pharm. Chem. II HORMONS

Hormones A chemical released from living cells that travels some distance to target tissues to have a biological effect  Secreted in very small amounts  Transported, usually, in the blood  Target cells have specific receptors  Regulates cell reactions by affecting gene expression (often gene transcription factors)

Hormones Steroids Sex hormones Adrenal corticol H Non-steroid Female sex HMale sex H Progesterone Estrogen Androgens

Sex hormones are biosynthesized in GONADS & adrenal glands Testes in male Ovaries &placenta in females  They control sexual maturity & reproduction.

Their activity is mainly controlled by the hormones released by anterior lobe of pituitary gland There are three types of sex hormones 1.Estrogens 2.Progestagene 3.Androgen

Female sex hormones Estrogens and progestrogenes are usually called female sex hormones as they produce in larger quantity in females.  Play imp role in reproduction and menstrual cycle  Used as contraceptive  Make characteristic physical difference in women And men.

Regulation of Estrogen and Progesterone The synthesis and secretion of estrogens is stimulated by Follicle-stimulating hormone(FSH), which is, in turn, controlled by the hypothalamic hormone & Gonadotropin releasing hormone(GnRH). Hypothalamus→GnRH→ Pituitary→FSH→Follicle→Estrogens. Hypothalamus→GnRH→ Pituitary→LH→ Corpus lutium→Both Progesterone and Estrogen.

Classifications 1.Estrogen(contains 18 carbon atoms):- i.Natural :- estradiol, estrone, estriol ii.Semi synthetic:- ethinylestradiol, mestranol iii.Synthetic:- diethylestilbestrol iv.Non-steroidal:- dienestrol, benzestrol, hexastrole.

Classifications 2.Progestrogen (C-19):- i. Natural :-Progesterone ii. Derivative of progesterone:- hydroxy.p, medroxy.p, dehydrogesterone, megastral acetate. iii. synthetic progesterone prepared from Androstanes: ethisterone, dimethisterone

ESTROGEN It stimulates the development of sex tissue and female secondary sex characters. Other biological activity of estrogen includes inhibitory effect on synthesis and release of gonadotropic hormone of anterior pituitary gland.  Ovary and placenta are the main sites of estrogen release  While adrenal cortex & testes also produce in small amount

Isolation: From urine of pregnant women, placenta, reproductive organs of mammals. Examples

Biosynthesis :- Estrogens are biosynthesized from cholesterol which in turn is synthesized in organ from acetyl coA. Mainly the synthesis takes place in ovary, placenta & adrenal cortex. In ovary, FSH acts on the preovulatory follicle to stimulate the biosynthesis. Thecal cells of the preovulatory follicle convert cholesterol into androgens, whereas the granulose cells convert androgen to estrogens. After ovulation, LH acts on the corpus lutium to stimulate both estrogen & progesterone biosynthesis & secretion.

pregnenolone cholesterol 17-α-hydroxypregnenolone

Metabolism:- Most of the metabolites are found in urine, even 50% of a dose of 17β- estradiol first goes to kidney via liver. Naturally occurring estrogens are weakly active when administered orally. As they are metabolized to a considerable extent by the liver, leading to low therapeutic effectiveness

S.A.R 1)sub on estrone nucleus modify estrogenic activity 2)OH group on 6,7,11 position reduces activity 3)Removal of oxygen from 3,17 position or epimerisation of 17 th OH group of estradiol decreases activity AB CD

4)D-ring is also not required for estrogenic activity Ex:-Diosynolic acid. which Is obtained from cleavage of estrone by a strong base

Steroidal estrogens(semisynthetic): Ethinyl estradiol and mestranol one successful method to overcome rapid oxidative inactivation of 17β-estradiol to estrone by 17β hydroxy steroid dehydrogenase in the liver is by blocking alcoholic function at C 17 with an appropriate substituent. Ex: Treatment of estrone with pot.acetylide in liq.ammonia results in ethinyl estradiol, times more potent than estradiol on oral administration. KC Liq.NH 3

Another semisynthentic estrogen, synthesized by similar route, is mestrenol. Both these mestrenol and ethinyl estradiol are used for contraceptive purposes.

Non steroidal estrogens:- The steroidal nucleus is not much essential for estrogenic activity. Many derivatives of stilbene which are more stable as potent estrogenic, used therapeutically.

Physiologic function : Estrogen acts on many tissues, such as those of reproductive tract, breast and CNS. Primary function is to stimulate the development of sex tissues. Growth of uterous is temporary. Estrogen can stimulate the proliferation of breast cells and promote the growth of hormone dependent breast cancer.

Pharmacology, side effects and clinical applications: Administration of estrogen to immature animals can increase the rate of sexual maturity. These hormones appear to prevent coronary atherosclerosis in women before menopause because of the alteration in the composition of circulating lipids. Oral and transdermal estrogens are used to treat female health problems. Adverse effect: Nausea & vomiting, anorexia & diarrhea.

PROGESTERON Progesterone is one of the most imp gestrogen. It is the imp hormone for maintaining pregnancy and normal menstrual bleeding.

In 1929 Allen and Corner developed the method to assay the progestational activity by removing corpus luteum shortly after contraception results in termination of pregnancy. It was isolated from corpus luteum, adrenal cortex, placenta & testes. During the full corpus luteum activity the human ovary can produces about 1000mg of progesterone daily.

Biosynthesis :- It is biosynthesized from cholesterol as follows oxidative cleavage of side chain double bond shift

Synthetic method :-From Diosgenin (Dioscorea species) acetolysis CrO3 oppenaur oxidation

The natural hormone has many drawbacks, including relative low potency on oral administration & I.V may cause lot of pain and irritation. Thus synthetic progesterone is prepared from Androstanes Ex: ethisterone, dimesterone

S.A.R 1)Steroid nucleus is necessory for progestin activity. 2)Synthetic progestins can generally devided into two classes namely androgen & 17α-hydroprogesterone In androgen series a 17α-substituents such as ethynyl, methyl,ethyl give orally active compounds.

3)Removal of methyl group from position 19 th leads to norethindrone with 10 times more progestetional activity than ethisterone. 4)Acetylation of 17β-OH group of norethindrone results in longer duration of action

5)Activity of nor ethindrone is increased by addition of CH 3 group at C-18 6) Unsaturation of ring B&C also increases activity. 7) Halogen or methyl sub at 6α &7α position increases activity.

Pharmacology, side effects and clinical applications: Primary function of progesterone with respect to myometrium is to stop the spontaneous rhythmic contraction of uterus. The effect of progesterone on the uterus is to maintain the fertilized ovum. And to suppress the myometrial contractions so that the embryo is not dislodged from uterus.

The high levels of progesterone produced by the corpus luteum and placenta during pregnancy act upon the hypothalamus through negative feedback mechanism to prevent the formation of new ova. This information led to studies involving progesterone and its analogs as contraceptive. Among the side effect seen with prog’ne are nausea, vomiting, drowsiness, spotting and irregular bleeding.

Contraceptive action of Estrogen and Progestin Estrogen and progestin could inhibit ovulation; it is found that combinations were highly effective. Although all the details of the process were still not completely known. It is believed that the combination suppress the production of LH and FSH,or both, by a feedback – inhibition process. Without FSH and LH ovulation is prevented. The process is similar to the natural inhibition of ovulation during pregnancy, caused by the release of estrogens & progesterone from placenta and ovaries. Alteration of the cervical mucus and endometrium serve actual contraception.

3 known mechanisms  Preventing ovulation is the main mechanism. The estrogen component is responsible for putting the ovaries into quiescence (sleep) and inhibiting ovulation (simulates the situation in pregnancy).  Reduce the ability of the sperm to penetrate into the cervix (by making the cervical mucus thicker)  Endometrium becomes less receptive to implantation (Selected Practice Recommendations for Contraceptive Use: WHO 2004)

Side effect :-Nausea, vomiting drowsiness and irregular bleeding. Dosage forms available: Oral contraceptive pill Combined oral contraceptive pill (COC) Progestogen only pill (POP) Contraceptive patch Contraceptive implant Contraceptive injection Emergency Hormonal contraception (EHC)

MALE SEX HORMONES Androgens are the male sex hormones These are synthesized mainly in testes adrenal cortex and also small amounts in ovary. The primary testicular androgen, testosterone has imp sexual and metabolic activity, it controls the development and maintenance of sex organs. Spermatogenesis is also depend on the testosterone function and secondary sexual characters.

Naturally occurring androgens includes androsterone and testosterone In 1931 Budendt isolated first androgen, androsterone. (1mg/15000 lit of human male urine) In 1934 David isolated the testosterone and tested its anabolic activity.

Biosynthesis:- Androgens are synthesized from cholesterol In testes and adrenal cortex,liver (from C-21steroids), small amounts from ovaries. Androgens are intermediates in the biosynthesis of estrogen

Cholesterol Pregnenolone 17α-hydropregnenolone dehydrogenase isomerasedehydrogenase 17α-hydroxylase Side chain cleavage 17,20 lyase

Metabolism :- The liver is the major site for metabolism of androgens. In urine,metabolites of major androgenic agent, testosterone are found. androsterone and its 5β-disterioisomer Etiocholamine are the major metabolites of testosterone. testosterone

S.A.R Steroid nucleus is necessary for androgenic activity. 1)Oxygen at 3 rd position not essential because basic nucleus,5α-androstane,has estrogenic activity.

2 ) 17β – oxygen is imp for attachment to the receptor Site & 17α- alkyl group is imp for preventing the metabolic changes at this position. Such 17α sub renders the comp orally active. Ex: 17α – methyltestosterone. 3)Increase in the length of side chain at 17 α position decreases the activity. 4) Halogen sub reduces activity except at 4&9 th position.

5) Esterification at C-17 increases duration of action on parentral administration. 6)Methyl group on 2 nd position yields potent anabolic activity Ex: dromostanolone 7) Introduction of heterocyclic ring also yields good anabolic agent. Ex: Stanazolol 8)Sub at 1,2,7,17 and 18 may results Compounds with clinical imp.

Pharmacology,side effects & uses: Normal growth and development Retention of nitrogen and other inorganic sub Used to restore or maintain secondary sexual characteristics. In the treatment of testes to descend, impotence, faulty spermatogenesis. Side effects : growth of hair on face, altering voice,development of muscular body.

Synthetic androgen Synthetic androgen : Testosterone has potent anabolic activity & it can not be used freely as it is having equally potent virilising activity. Clinically used anabolic steroids are ethylstrenol, oxandrolone which are derivative of testosterone & methyl testosterone.

CONCLUSION : Thus it is necessary to control the rate of population growth by the application of Hormones as more safer contraceptive method by understanding basic mechanism behind it.

References: Organic chemistry of natural products, vol-II by Gurdeep R Chatwal. Org.chem.,Chemistry of organic natural products., by O.P Agarwal. Burgers medicinal chemistry, Drug discovery & design, Vol-IV, V-Edition Med. Chem,vol-II,Kadam & Bhothara health/publications/spr/spr.pdf health/publications/spr/spr.pdf