The gonadal hormones and inhibitors J.Cermanová

Sexual hormones are two types: protein and steroids Steroids are liposolubile - can easily diffuse trough target cells have intra - cellular receptors in bloodstream can circulate only if bound to non-specific proteins – albumin or to specific protein – SHBG (sex hormone binding globulin) Proteins are hydro soluble cannot penetrate the cells, they need membrane receptor circulate freely in the blood

Ovarian hormones Steroids Estrogens estrogenic activity is shared by a large number of chemical substances . Natural Estrogens estradiol, estrone, estriol Although some estrone is produced in the ovary, most estrone and estriol are formed in the liver from estradiol or in peripheral tissues from androstenedione and other androgens

In addition to the steroidal estrogens, 2. Synthetic Estrogens In addition to the steroidal estrogens, a variety of nonsteroidal compounds with estrogenic activity have been synthesized and used clinically. These include dienestrol, diethylstilbestrol, benzestrol, hexestrol, methestrol, methallenstril and chlorotrianisene This group is represented both steroidal as well as nonsteroidal agents The most widely used in clinical practice is diethylstilbestrol

Pharmacodynamics plasma estrogens are bound to sex hormone binding globulin, from which they dissociate to enter the cell and bind to their receptor. Two genes code for estrogen receptors, which are members of the superfamily of steroid and thyroid receptors. The estrogen receptors are found predominantly in the nucleus, bound to proteins, that stabilize it.

Effects of Estrogens they stimulate the development of the female maturation they stimulate the development of the vagina, uterus, and uterine tubes as well as the secondary sex characteristics endometrial effects development of endometrial lining effects on blood coagulation e. enhance the coagulability of blood  increased circulating levels of ff. II, VII, IX and X and decreased antithrombin III.

responsibility for maintenance of the normal metabolic effects responsibility for maintenance of the normal structure of the skin and blood vessels in women decrease the rate of resorption on bone (but not stimulate bone formation) e. alter the production and activity of many proteins  increaseed circulating levels of thyroxine, estrogen, testosterone, iron, cooper e. alter the plasma lipids  increase in the HDL, and a reduce in the LDL, and reduce plasma cholesterol levels

other effects : e. induce the synthesis of progesterone receptors e. facilitate the loss of intravascular fluid into the EC space, producing oedema. The resulting decrease in plasma volume causes a compensatory retention of sodium and water in kidney.

Clinical Uses Primary hypogonadism for replacement therapy in e. deficiency patients Postmenopausal hormonal therapy prevention of osteoporosis administration of e. is associated with an increased risk of endometrial carcinoma to stop excessive uterine bleeding due to endometrial hyperplasia

Adverse Effects nausea brest tenderness hyperpigmentation migraine headaches cholestasis hypertension gall blader colic

Progestins . Natural Progestins The most important progestin in humans progesteron. in the ovary, progesterone is produced primarily by corpus luteum. 2. Synthetic Progestins multiple group Some compounds are active by p.o. route.

Pharmacodynamics The mechanism of action of progesterone is similar to that of other steroid hormones. Progestins enter the cell and bind to progesterone receptors that are distributed between the nuncleus and the cytoplasmatic domains.

Effects of Progestins little effect on protein metabolism stimulation of lipoprotein lipase activity effect on carbohydrate metabolism: - p. increases basal insulin levels and the insuline response to glucose. - in the liver p.promotes glycogen storage, possibly by facilitating the effect of insulin. - promotes also ketogenesis p.increased the body temperature in humans

Clinical Uses for hormon replacement therapy hormonal contraception treatment of premenstrual syndrome

Hormonal contraception Two types of preparations are used for oral contraception: / combination of estrogens and progestins 2/ continuous progestin (without estrogens) Mechanism of action: selective inhibition of pituitary function that result in inhibition of ovulation. changes in the cervical mucus, in the uterine endometrium, and in motility and secretion in the uterine tubes decrease the likehood of conception and implantation.

Other Effects the inhibition of pituitary gonadotropin secretion serious thrombembolic risk increasing TAG and cholesterol small increases in cardiac output  associated with systolic and diastolic BP hyperpigmentation

Adverse Effects Mild AE: nausea, mastalgia – breast pain changes in serum proteins hadeache withdrawal bleeding may occurs Moderate AE bleeding (progestin alone) weight gain increased skin pigmentation – chloasma, acne vaginal infection amenorrhea

Severe AE: Vascular disorders Venous thrombembolic disease Myocardial infarction Cerebrovascular disease ! CAVE 35 years of age or older, heavy smokers ! GIT disorders Cholestatic jaundice Depression Cancer – this efect is not uniform was describe higher risk of cervical CA on the other hand reduction of endometrial and ovarian CA

Estrogen and Progesterone inhibitors and antagonists Tamoxifen competitive partial agonist inhibitor of estradiol at the estrogen receptor is extensively used in paliative treatment of advanced breast CA in postmenopausal women Clomiphene partial agonist, that also acts as a competitive inhibitor of endogenous estrogens use as an ovulation-inducing agent

Danazol - derivate of ethisterone - used to suppress ovarian function Anastrazole selective nonsteroidal inhibitor of aromatase ( the enzyme required for estrogen synthesis) used in treatmen of breast CA in the case of resistance to therapy with tamoxifen others aromatase inhibitors in clinical trials: letrozole, fadrozole

II. Testicular hormones Androgens and Anabolic Steroids the most important androgen secreted by testis is testosterone. in many target tissues, testosteron is converted to dihydrosterone by the 5 α- reductase. - like other steroids testosterone acts intracellulary. in some tissues occurs the conversion of t. to estradiol. - androstenedion, dehydoepiandrosterone (DHEA)and dehydoepiandrosterone sulfate (DHEAS) are also produced in significant amounts in humans, though largely in the adrenal gland rather in the testes.

Testosterone and derivatives have been used for Synthetic Steroids with Androgenic and Anabolic Action are derivatives of testosterone – propionate, enanthate, undercaonate, or cypionate Testosterone and derivatives have been used for their anabolic effects as well as for the replacement of testosterone deficiency.

Clinical Uses Androgen replacement therapy in men Gynecologic disorders androgens are sometimes given in combination with estrogens for replacement therapy in the postmenopausal women to eliminate the endometrial bleeding that may occur when only estrogens are used Use as protein anabolic agents to reverse protein loss after trauma, surgery or immobilization and in patients with debilitating diseases

Anemia as aplastic anemia Osteoporosis Use as growth stimulators a separate problem is abuse of androgens in sport Adverse effects: masculinizing actions which are most noticeable in women and prepubertal children hirsutism, acne, depression of menses, deepening of the voice….

Androgen supression and antiandrogens - treatment of advanced prostatic CA leuprolide acetate, goserelin gonadotropin-releasing hormones, which produce in continuous administration gonadal supression The therapy often requires orchiectomy or large doses of estrogens to reduce available androgen. AE: gynecomastia

Antiandrogens The potential usefulness of antiandrogens is for the treatment of patients producing excessive amounts of testosterone. Ketoconazole - used primarily for the tretment of fungal disease - is an inhibitor of adrenal and gonadal steroid synthesis inhibits P 450scc - cholesterol side chain cleavage enzyme This compound has been used with succes for the treatment of patients with Cushing syndrome.

Finasteride - inhibitor of 5 α- reductase, reduces dihydrotestosterone levels Receptor inhibitors Cyproterone - for treatment of hirsutism in women, for decrease excessive sexual drive in men Flutamide, bicalutamide for treatment of prostatic CA Spironolacton competitive inhibitor of aldosterone

Therapy of Osteoporosis Osteoporosis is defined as abnormal loss of bone predisposing to fractures - is most common in postmenopausal women, but also occurs in men. it may occur as a side effect of chronic administration of glucocorticoids as manifestation of endocrine disease such as thyreotoxicosis or hyperaldosteroidism as manifestation of alcohol abuse….

The postmenopausal form of osteoporosis may be accompanied by lower 1,25(OH)2 D levels and reduced intestinal calcium transport. This form appears to be due estrogen deficiency and is best treated with cyclic doses of estrogen. Vitamin D is often employed in addition to dietary. Calcium supplementation.

Etidronate, pamidronate and alendronate Bisphophonates Etidronate, pamidronate and alendronate These drugs exert a variety of effects on bone mineral homeostasis. Able to dissolute of hydroxyapatite crystals within and outside the skeletal system However the exact mechanism by which they selectively inhibit bone resorption is not clear