Steroids Sex (Gonadal) Hormones Agonist & Antagonists 8 أ.م.د. وحدة اليوزبكي Head of Department of Pharmacology- College of Medicine- University of Mosul- 2014

Objectives - At the end of this lecture, students should be able to : 1- List steroids sex (Gonadal) hormones 2- Explain mechanism of action of steroid hormones 3- Identify pharmacokinetic of steroid sex hormones 4- List female sex hormones (preparations, clinical uses, adverse effects) 5- State the antagonist of female sex hormones - At a level accepted to the quality assurance standards for the College of Medicine/ University of Mosul.

Steroids Sex (Gonadal) Hormones Agonist & Antagonists Female sex hormones Estrogen & Progesterone Male sex hormones Androgenic & Anabolic

Mechanism of action of steroid hormones

Notes 1- The steroid hormones may elicit the synthesis of different RNA species in diverse target tissues and are therefore both receptor-and tissue-specific. 2- Compounds that occupy the receptor without causing translocation into the nucleus or the replenishment of receptors act as antagonists e.g. spironolactone to aldosterone cyproterone to androgens clomiphene to oestrogens

Pharmacokinetic of steroid sex hormones 1- Well absorbed through mouth and skin (factory workers need protective clothing). 2- Most undergo extensive hepatic metabolism. 3- Some has enterohepatic circulation (especially for estrogen). 4- Sustained – release depot preparations are used. 5- Carried in the blood bound to steroid hormone binding globulin (SHBG).

Female Sex Hormones 1- Estradiol, Estriol and Estrone - natural, given orally. 2- Ethinylestradiol : synthetic agent (1 st choice for contraceptive pills), given,orally 3- Conjugated estrogen (premarin), orally active mixed natural estrogen. 4- Estropipate, synthetic conjugate, orally active. 5- Stillbesterol (diethylstilbestrol). The 1 st synthetic estrogen. Now its used confined to androgen dependent cancer of prostate.

Physiological effects of estrogen A- Natural Estrogen: 1- Responsible for normal development of female genital tract, of the breast o sex characteristic. 3- Necessary for the maintenance of normal pregnancy and for accompanying breast hyperplasia.

B- Synthetic (Pharmacological) estrogen 1- Some degree of retention of salt and water edema and hypertension. 2- Enhance coagulability of blood by circulating factors II, III, IV, V & antithrombin. 3-Increase build up of bone. 4- Inhibition of gonadotrophin release from ant. pituitary prevent maturation of ovarian follicle (base of oral contraceptives).

Clinical uses of Estrogen 1- Replacement therapy in hypo ovarian condition. 2- Post menopausal symptoms (flushes, dry vagina). Post menopausal hormone replacement therapy (H.R.T) given for 2 aims: a- To reduce every day symptoms of estrogen deficiency (hot flushes, lethargy, depression, and dry vagina). b- To prevent the long term complications (Osteoporosis and CVD). 3- Contraception (combined with progesterone). 4- Androgen dependent carcinoma as prostatic cancer. 5- Menstrual disorders. 6- Reduce sexual urge in male.

Adverse effect of estrogen 1- GIT disturbance (diarrhea, vomiting, anorexia). 2-Prolonged use Na and water retention hypertension. 3- Increase incidence of thromboembolism (natural < synthetic). 4- Withdrawal bleeding. 5- In male reduce libido, impotence and gynaecomastia. 6-Cancer of endometrium (so give progesterone with it). 7- Cancer of breast incidence may increase. 8- Increase blood glucose. 9- In pregnancy vaginal cancer in offspring girl. 10- Estrogens added to cosmotic skin and hair may cause precautious puberty in children, and post menopausal bleeding in female and gynaecomastia in male adult. 11- CNS disorders: depressions headache and migraine.

Antiestrogen (Estrogen Antagonist) 1- Clomiphene citrate (clomid) 2- Cycofenil. 3- Tamoxifen. (Nolvadex). Uses: These selective antagonist of Eestrogen used for: 1- Induction of ovulation (clomifene and cyclofenil). 2- Blocks stimulation of estrogen receptor positive Ca. of breast (tramoxifen).

1. Clomifene (clomide) - Structurally related to stilbesterol. - It is weak estrogen agonist (partial agonist) - It is a weak estrogen agonist having less activity than natural estrogens, so that its occupation of receptors results in antagonism, i.e. it is a partial agonist. - Clomifene blocks hypothalamic estrogen receptors so that the negative feedback of natural estrogens is prevented and the pituitary responds by increased secretion of gonadotrophins, which may induce ovulation.

Side effects of Clomifene 1- Ovulation and multiple pregnancy (mainly). 2- Ovarian enlargement. 3- Eye disturbance. 4- Nausea, vomiting,hot flushes, tension, headache. 5- Reversible alopecia. Uses of Clomifene : - Given during the early follicular phase menstrual cycle on day 2-6 of cycle.

2- Cyclofenil act as clomifen. 3- Tamoxifen - Competitive nonsteroidal estrogen antagonist. - Used mainly in estrogen dependent breast cancer.

Progesterone Preparations: 1- Progesterone and its derivatives: Hydroxyprogesterone, medroxyprogesterone. 2- Testosterone derivatives: norethisterone, levonorgestrel.

Clinical uses of progesterone 1- Contraception either combined with estrogen or alone. 2- Prevention of threatened abortion. 3- Menstrual disorders eg menorrhagia, dysmenorrhea, or premenstrual tension. 4- Breast and endometrial cancer. 5- Treatment of endometriosis.

Side effects of progesterone 1- Edema and hypertension. 2- Depression. 3- Hyperlipidaemia (androgen derivative progesterone). 4- Synthetic progestin has androgenic activity (Acne, weight gains and hirsutism).

Antiprogesterone 1- Mifepristone - Pure competitive antagonist of progesterone. - Effective in termination of early pregnancy (combined with PG) vaginally (gemeprost). Side effects: Heavy bleeding, abdominal pain.

2- Danazole Action: It is relatively selective inhibitor of pituitary gonadotrophin secretion (LH & FSH) so decrease the ovarian function so causing atrophic changes in endometrium both of the uterus and elsewhere ectopic endometrium (endometriosis). Uses: 1-Treatment of endometriosis in female. 2- Spermatogenesis in male. 3- Fibrocystic mastitis, gynecomastia, menorrhagia and hereditary angioedema.