Sex (, progestin and مادة االدوية –المرحلة الثالثة: د. عماد نعمان شريف • • Objective :- • - Know the used as and antagonist.- • - Know the pharmacokinetic, pharmacodynamic , indication, side effect, contraindication for drug used as estrogen, profgesterone and androgen and antagonists. • - How treatment of erectile dysfunction.

SEX : (estrogen, progestin and androgen). • Sex hormones are (fat soluble compounds) that control sexual maturity and reproduction. These hormones are produced mainly by the endocrine glands. The endocrine glands in females are ovaries and those in males are testes. While both males and females have all types of hormones present in their bodies, females produce the majority of two types of hormones, and , while males produce mainly such as . Most androgens produced by females are converted to estrogens and some androgens in males are also converted to estrogens. Sex hormones are synthesized from cholesterol (a fatty acid) and other compounds and secreted throughout a person's lifetime at different levels. Their production increases at puberty and normally decreases in old age.

• Hormone Production; • The production of hormones are a complex process. At puberty, the brain's hypothalamus gland produces increased amounts of -releasing hormone. This hormone stimulates the nearby pituitary gland to release two other hormones: follicle-stimulating hormone (FSH) and (LH). Finally, these two hormones signal the sex glands (gonads) to produce the sex hormones. • Female Reproductive cycle: • Females produce three estrogens: , estriol, and estrone. These estrogens stimulate growth of the ovaries and begin preparing the for . Estrogens also control the body's secondary sex characteristics, including breast and pelvic development and the distribution of fat and muscle. Progesterone maintains uterine conditions during pregnancy. It also acts on the central nervous system in a way that isn't yet understood. During the monthly reproductive cycle, FSH stimulates growth of an ovarian body called the graafian follicle. The follicle encloses the egg. LH aids in the rupture of the follicle, sending the egg to the fallopian tubes. LH also promotes growth of the corpus luteum (a yellow, progesterone- secreting mass of cells that forms from an ovarian follicle after the release of a mature egg) as the ovary prepares to release the egg into the uterus. • If no pregnancy occurs within 10-12 days, the corpus luteum withers and the uterus shed the blood supply that was formed to nourish a . This shedding of the uterine lining and blood supply is called menstruation (the period). The production of estrogens and progesterone drops dramatically, and the cycle begins again. • Male Reproduction • In males, LH stimulates the development of the testes. The testes produce the androgens testosterone and . When FSH activates the testes' sperm-forming cells, testosterone maintains the process of forming sperm. This is the ten-week process results in sperm constantly ready for release by ejaculation from the penis. The androgens also promote the secondary sex characteristics of muscle growth, lowered voice range, the Adam's apple, and increased body hair. Estrogen:-

• Action:- • 1- increase growth, development of uterus, fallopian tube, and oviduct. • 2- Increase growth, development of myometherium during puberty and pregnancy. • 3- Increase endothelial lining of endometherium (proliferative phase). • 4- Increase epithelial layer, secretion of . • 5- Increase duct formation of breast (prepare for lactation). • 6- Decrease bone resorption, but has not effect on bone formation. • 7- Increase HDL, decrease LDL and TG. • = Estrogen therapy:- • Indication: • 1- Hormonal replacement therapy. • 2- Reduces or eliminates several symptoms of such as hot flushes, disturbed sleep resulting from hot flashes and vaginal dryness. • 3- Oral contraceptive in combination with progesterone. • 4- . • 5- Primary dysmenorrheal. • 6- and . • 7- Carcinoma : It is androgen dependent tumors and estrogens acts by suppressing the androgen production. • Adverse effect: • 1- Nausea, headache and breast tenderness. • 2- Postmenopausal uterine bleeding. • 3- The risk of thromboembolic events, peripheral , hypertension, myocardial infarction, breast and endometrial cancer. • Estrogen formulations and route of administration: Oral, , subcutaneous implants, vaginal (ring, cream, or pessary), patch, gel, nasal spray which is delivers 300 micrograms of estradiol daily. • Preparations of estrogens: • = Estrogen. • - Ethinyl estradiol • - Estradiol, estrone and estriol. • - Estrasorb. • - Conjugated estrogens (premarin). • - Estropipate (piperazine estrone sulphate). • - (stilbestrol). • = Selective estrogen receptor modulators (SERMS): Combine estrogenic and antiestrogenic properties (, clomiphene, tamoxifene, toremifene and ). They readily absorbed after oral absorption. • - Clomiphene: Is structurally related to diethylstilbestrol; it is a weak estrogen agonist less activity than natural estrogens, • Mode of action: It act as a partial estrogen agonist and interferes with the negative feedback of estrogen on the hypothalamus. This effect thereby increases the secretion of gonadotropin-releasing hormone and leading to stimulating . • Clomiphene is administered during the early follicular phase of the menstrual cycle (50mg daily on days 2-6) and is successful in inducing ovulation in about 85% of women. • Uses: • - Treat infertility associated with anovulatory cycles , but not effective in women with ovulatory dysfunction due to pituitary or ovarian failure. • Side effect: Are dose related. • 1- Headache, nausea, vasomotor flushes, visual disturbance, and ovarian enlargement. • 2- Multiple ovulation with multiple pregnancy may occur 3-5%. • 3- There have been reports of an increased incidence of ovarian carcinoma following multiple exposure, and the number of consecutive cycles for which clomiphene may be used to stimulate ovulation should be limited to 12. • - Cyclofenil: Acts similarly to clomiphene. • Tamoxifene: Is a non-steroidal competitive estrogen antagonist on target organs as breast tissue. Although available for anovulatory infertility (20 mg daily on days 2,3,4, and 5 of the cycle). • Uses: • 1- Its main use in the treatment of estrogen-dependent . • 2- Is currently used in the palliative treatment of metastatic breast cancer in postmenopausal women. • 3- It may also be used as adjuvant therapy following mastectomy or radiation in breast cancer and as a prophylactic therapy to reduce the risk of breast cancer in high risk patients. • adverse effects:- • 1- Hot flashes and nausea. • 2- Menstrual irregularities and vaginal bleeding • Raloxifene: Has antiestrogenic effects on breast and endometerium, but estrogenic effects on bone and is used for prevention and treatment of osteoporosis. It is approve for the prophylaxis of breast cancer in high risk women, but increases risk of deep-vein thrombosis, pulmonary embolism and retinal vein thrombosis, in addition raloxifene should be avoided in women who are or may become pregnant. • Tibolone: Is licensed for short-term treatment of osteoporosis. • Progesterone:-

• Progesterone:- • Action: • 1- Maintain uterine condition during pregnancy. • 2- Decrease uterine motility and contraction. • 3- Increase mammary gland action. • 4- Negative feedback on LH which decrease ovulation. • 5- Thick, viscous secretion in cervix. • 6- Decrease aldosterone effect. • 7- Decrease plasma levels of many amino acids. • Indication of Progestational Agents (therapy)in clinical practice: • 1- Hormonal deficiency. • 2- Dysfunctional uterine bleeding. • 3- A part from contraceptive, they are generally used with estrogen, either in combination or in a sequential manner. • 4- Dysmenorrheal and endometriosis. • 5- Infertility. • Adverse effect: • - Headache, depression, weight gain and change in lipido. • - Some type can increase the ratio of LDL to HDL cholesterol and cause acne and hirsutism. • - Injectable acetate has been associated with an increased risk of osteoporosis. • Preparation: • 1- Natural. The most side effect are fatigue and sedation. • 2- Synthetic • - Oral: Norethindrone, norethindrone acetate, , , , , . • - Suppositories or pessaries: Progesterone. • - Injectable: Progesterone, hydroxyprogesterone, medroxyprogesterone. :-

• , also called an antiprogesterone agent, is a type of hormone antagonist which antagonizes or suppresses the action of progesterone in the body. • Menstruation (in its luteal phase) is dependent on progesterone, and uterine bleeding follows antagonism of progesterone. Pregnancy is dependent on progesterone (for implantation, endometrial stimulation, suppression of uterine contraction and placanta formation), and follows progesterone antagonism in early pregnancy. • : Is a progesterone antagonist with partial agonist activity and has potent antiglucocorticoid activity. Is orally active. • Adverse effect: Nausea and vomiting, dizziness, asthenia, abdominal pain, uterine bleeding may be heavy. It also offers the opportunity for mid-trimester terminations. • Therapeutic uses: • 1- Termination of pregnancy: • 2- Cervical ripening: • 3- Postcoital contraceptive: • 4- Induction of labour: • 5- Cushing's syndrome: • 6- Once a month contraceptive: ANDROGENS:-

• 1- Testosterone is the main natural androgen which is essential for male sex characteristics • 2- Testosterone is secreted by the leydig cells of the testis, and normal adult male testosterone production amounts to 2.5 - 11mg/24hr. • 3- It circulate highly bound to a hepatic glycoprotein called sex hormone binding globulin (65%) and loosely bound to albumin (33%). Only 1-2% of circulating testosterone is unbound and freely available to tissues. • 4- It is converted by hydroxylation to the active (DHT) by 5-alpha reductase. • 5- Testosterone is necessary for normal spermatogenesis, for the development of the male secondary sex characteristics, sexual and for the growth at puberty of the genital tract. • Indication for androgen therapy: • 1- : • 2- Carcinoma of breast: Which has oestrogen receptors, may respond to testosterone therapy. It acts as an anti-oestrogen. • 3- Hereditary angioneurotic oedema. • 4- Female androgen insufficiency. • Preparations and choice of androgens: • Androgen are available for oral, buccal, transdermal or depot administration. • = Oral preparation: • - : • - . • = Parenteral preparation: • - Sustanon: • - and testosterone epionate: • =Transdermal preparation: • = Buccal preparation: • Female androgen insufficiency: • 1= : • 2= (danol): • Danazol is a derivative of the progesterone, , it has partial agonist androgen activity, it has little activity. it acts on the pituitary gland in the brain, it inhibits the production of hormones called gonadotropins by the pituitary gland. Gonadotrophins normally stimulate the production of sex hormones such as oestrogen and progestogen, which are responsible for body processes such as menstruation and ovulation. By decreasing the production of these sex hormones, danazol can be used to treat disorders that are associated with disturbances in hormone production. Danazol capsules should be swallowed whole with a drink of water. They can be taken either with or without food. Danazol is only used for women whose condition has not responded to other forms of treatment. It is recommended that a treatment course should only last three to six months. Unwanted androgenic effects occur in women (acne, hirsutism, and rarely enlargement of the clitoris). • It is used chiefly for: endometeriosis, fibrocystic mastitis, gynaecomastia, precocious puberty, menorrhagia and hereditary angio-oedema. In male it reduces spermatogenesis. • Adverse effect of androgen therapy: • 1- In female: It can caused masculinization, acne, growth of facial hair, deepening of voice, male pattern baldness and excessive muscle development. Menstrual irregularities may also occur. Testosterone should not be used in pregnant women because of possible of the female fetus. • 2- In male: Excess androgens can cause priapism, impotence, decreased spermatogenesis and . It also stimulate growth of prostate. • 3- In children: It can cause abnormal sexual maturation and growth disturbance resulting from premature closing of the epiphyseal plates. • 4- Genetic effect: It is increased serum LDL and lower serum HDL and potentially increase the risk for premature coronary heart disease. It can also cause fluid retention, leading to edema. • 5- In athletes: Use of high dose of anabolic steroids may result in reduction of testicular size, hepatic abnormalities, increased aggression (roid rage), major mood disorders. • - Contraindicated in carcinoma of the prostate. • - Monitoring during treatment include regular measurement of prostate specific antigen (PSA). Haemoglobin should also be monitored to avoid polycythaemia.

• Adverse effect of androgen therapy: • 1- Increased may lead to undesirable sexual activity. • 2- Virilizing effects in women . It can cause menstrual irregularities, growth of facial hair, and coarsening of voice. If therapy is stopped after short of duration, then side effects subside. With long term use, other adverse reaction seen are male pattern baldness, excessive body hair, muscle development and hypertrophy of clitoris and feminizing effect in male. • 3- A weak salt and water retaining activity, which is not often clinically important. • 4- injury (cholestatic jaundice) can occur particularly with 17α-alkyl derivative (, danazole, ). • 5- Effect on blood lipids are complex and variablE. • 6- In patients with malignant disease of bone, androgen administration may be followed by hypercalcaemia. • - Contraindicated in carcinoma of the prostate. • - Monitoring during treatment include regular measurement of prostate specific antigen (PSA). Haemoglobin should also be monitored to avoid polycythaemia. (androgen antagonist):- • Estrogen and are physiological antagonist to androgens It is blocked by its receptor blockade and inhibition of 5-alpha reductase that converts testosterone into DHT. It can also be inhibited by gonadotropin- releasing hormone or its analogue, such as leuprolide, which blocks the synthesis of LH leading to fall in testosterone levels. • 1- : • It is specific receptor antagonists of androgen, it is a derivative of progesterone, its combination of structural similarities and differences results in the following, (mode action): • - Competition with testosterone for receptors in target peripheral organs (but not causing feminization as do estrogen); it reduces spermatogenesis even to the level of azospermia, abnormal sperm occurs during treatment. • - Competition with testosterone in the CNS, reducing sexual drive and thoughts, and causing impotence. • The dose of 100mg/day causes 50% decrease in plasma concentration of LH and FSH and 75% decrease in testosterone levels. • Uses: • - Reducing male hypersexuality. • - Prostatic cancer. • - Sever female hirsutism. • 2- : It is used in prostatic carcinoma, usually in combination with gonadorelins (goserelin). • 3- and : Are potent, orally active and non-steroidal antiandrogens available for use in conjugation with the gonadorelins (ex. goserelin) in the treatment of prostatic carcinoma. • 4- and : Are 5- α -reductase inhibitor which inhibit conversion of testosterone to dihydrotestosterone, they are useful in the treatment of benign prostatic hypertrophy. • 4- : Has activity and may help hirsutism in women. • 5- (antifungal): Interferes with androgen and corticosteroid synthesis and may be used in prostatic carcinoma and Cushing's syndrome. Erectile dysfunction (ED):

• Mechanism of action: Stimulation of the nerve endings in the endothelial cells of erectile tissue (corpus cavrenosum) cause release of nitric oxide (NO). the NO then diffuses out of the cell and then acts with iron in the guanylyl cyclase to produce the intracellular mediator guanosine mono phosphate (GMP) from guanosine triphosphate (GTP) which act as a vasodilator by relaxing smooth muscle in the blood vessels of the corpus cavernosum. This lead to increased blood flow into penis and hence an erection. • The dose of sildenafil for ED is 25 – 100 mg taken not more than once per day between 30miniutes and four hours prior to sexual intercourse. The dose for pulmonary hypertension is 20mg three time daily. • Common adverse effect is headache, flushing dyspepsia, nasal congestion, palpitations and photophopia. Serious side effect is severe hypotension, and myocardial infarction. • Protein inhibitors inhibit the of sildenafil and caution should be exercised if co- administered. • Sildenafil and other agents of this class should not be taken by patients who are taking nitric oxide donors, nitrate and nitrites for heart disease and with history of recent heart attack or stroke, severely impaired cardiac, hepatic and renal function as well as those with inherited retinal disorders. • Drugs that may cause impotence:- • a- alcohol. b- Amphetamine • c- Antihypetensive drug (atenolol, bumtamide). d- Corticosteroid. • e- H2-blockers as . f- Halopridol. • h- Lithium. g- Opiate as codeine, methadone. • n- Some antidepressant as buspirone, amoxapine. • Most commonly drug agent used for male impotence: • 1- Alprostadil. 2- Danazol. • 3- Methyl testosterone. 4- Oxymetholone. • 5- Papaverine. 6- Testosterone • 7- Phosphodisterase inhibitors as sildenafil, verdanafil, tadalafil Reference

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