The Gonadal Hormones & Inhibitors By S. Bohlooli, PhD School of Medicine, Ardabil University of Medical Sciences

Biosynthesis, metabolism of estrogens and testosterone

Other sources of estrogens Diet Estrogen-mimetic compounds (flavonoids) are found in many plants, including: saw palmetto Soybeans Some compounds used in the manufacture of plastics bisphenols, alkylphenols, phthalate phenols associated with an increased breast cancer

Compounds with estrogenic activity

Commonly used estrogens. Average Replacement Dosage Ethinyl estradiol mg/d Micronized estradiol1-2 mg/d Estradiol cypionate2-5 mg every 3-4 weeks Estradiol valerate2-20 mg every other week Estropipate mg/d Conjugated, esterified, or mixed estrogenic substances: Oral mg/d Injectable0.2-2 mg/d TransdermalPatch Quinestrol mg/week Chlorotrianisene12-25 mg/d Methallenestril3-9 mg/d

OVARIAN HORMONES Estrogens Mechanism of action Effects Modifies serum protein levels Decrease bone resorbtion Enhance blood coagulability Increase in HDL Increase triglycerides and slight decrease in LDL Clinical use Treatment of hypogonadism Hormone Replacement Therpay (HRT) As component of hormonal contraceptives

OVARIAN HORMONES: Estrogen Toxicity Uterine Bleeding Increased risk of endometrial cancer Increased risk of breast cancer and cardiovascular events Nausea, breast tenderness, thromboembolic events, gall bladder disease, Hyperpigmentation Hypertension DES: vaginal adenocarcinoma in the daughters

OVARIAN HORMONES Progestins Mechanism of action Effects Affect metabolism of carbohydrate Stimulate fat dispostion Clinical use As contraceptive In HRT program In assisted reproductive technology program

OVARIAN HORMONES: Progestins Toxicity: Is low Increase in blood pressure Decrease in HDL Decrease in bone density Delayed resumption of ovulation

Progesterone and some Progestational agents in clinical use

Activities 1 Route Duration of Action Estrogenic Androgeni c AntiestrogenicAntiandrogenicAnabolic Progesterone and derivatives ProgesteroneIM1 day--+-- Hydroxyprogesterone caproate IM8-14 dayssl --- Medroxyprogesterone acetate IM, PO Tabs: 1-3 days; injection: weeks Megestrol acetatePO1-3 days Ethinyl testosterone derivatives DimethisteronePO1-3 days--sl-- The usual routes of administration and durations of action of the synthetic progestins(1)

DesogestrelPO1-3 days----- Norethynodrel 2 PO1-3 days+---- Lynestrenol 3 PO1-3 days++--+ Norethindrone 2 PO1-3 dayssl++-+ Norethindrone acetate 2 PO1-3 dayssl++-+ Ethynodiol diacetate 2 PO1-3 dayssl++-- L-Norgestrel 2 PO1-3 days Nortestosterone derivatives Activities 1 RouteDuration of ActionEstrogenicAndrogenicAntiestrogenicAntiandrogenicAnabolic The usual routes of administration and durations of action of the synthetic progestins(2)

OVARIAN HORMONES Hormonal contraceptives Mechanism of action Inhibition of ovulation Effects on cervical mucus glands, uterine tubes and endometrium Other clinical use and beneficial effects In primary hypogonadism In treatment of acne, hirsutism Dysmorrhea, endometriosis Decreased risk of ovarian cysts, ovarian and endometrial cancer Benign breast disease, rheumatiod arthritis

OVARIAN HORMONES: contraceptives: adverse effect MILD ADVERSE EFFECTS Nausea, mastalgia, breakthrough bleeding, and edema are related to the amount of estrogen in the preparation. Increases in sedimentation rate are thought to be due to increased levels of fibrinogen. Headache is mild and often transient. Withdrawal bleeding sometimes fails to occur

OVARIAN HORMONES: contraceptives: adverse effect MODERATE ADVERSE EFFECTS Breakthrough bleeding is the most common problem in using progestational agents alone Weight gain is more common with the combination agents containing androgen-like progestins Increased skin pigmentation may occur Acne may be exacerbated by agents containing androgen- like progestins Hirsutism may also be aggravated by the "19- nortestosterone" derivatives Ureteral dilation similar to that observed in pregnancy has been reported Vaginal infections are more common Amenorrhea occurs in some patients

OVARIAN HORMONES: contraceptives: adverse effect SEVERE ADVERSE EFFECTS Vascular disorders: Thromboembolism Myocardial infarction Cerebrovascular disease Gastrointestinal disorders cholestatic jaundice have been reported in patients taking progestin-containing drugs hepatic adenomas Depression Cancer

OVARIAN HORMONES: contraceptives: Contraindications & Cautions Contraindications thrombophlebitis, thromboembolic phenomena, and cardiovascular and cerebrovascular disorders The oral contraceptives may produce edema Estrogens may increase the rate of growth of fibroids Cautions aware of an important interaction that occurs with antimicrobial drugs potent inducers of the hepatic microsomal metabolizing enzymes

Estrogen (mg)Progestin (mg) Monophasic combination tablets Alesse, Aviane, Lessinea, LevliteEthinyl estradiol0.02L-Norgestrel0.1 Biphasic combination tablets Ortho-Novum 10/11, Necon 10/11 Days 1-10Ethinyl estradiol0.035Norethindrone0.5 Days 11-21Ethinyl estradiol0.035Norethindrone1.0 Triphasic combination tablets Enpresse, Triphasil, Tri-Levlen, Trivora Days 1-6Ethinyl estradiol0.03L-Norgestrel0.05 Days 7-11Ethinyl estradiol0.04L-Norgestrel Days 12-21Ethinyl estradiol0.03L-Norgestrel Daily progestin tablets Ovrette D,L-Norgestrel Implantable progestin preparation Norplant System L-Norgestrel (six tubes of 36 mg each) Some oral and implantable contraceptive agents in use

Anitsteogens and antiprogestins SERMs Tamoxifen Raloxifen Clomiphen Antiprogestins mifepristone Synthesis inhibitors Aromatase inhibitors: anastrazole, exemestane Danazol Pure estrogen receptor antagonists Fulvestrant Gonadotropin releasing hormone analogs

Control of ovarian secretion and the actions of its hormones

Tomxifen: first selective estrogen receptor modulator (SERM) Palliative treatment of breast cancer Chemoprevention of breast cancer May increase the risk of endometrial cancer.

MIFEPRISTONE The drug has luteolytic properties An effective emergency postcoital contraceptive To terminate early pregnancies

DANAZOL Mechanism of action: Weak progestational, androgenic, and glucocorticoid activities Bind to sex hormone-binding and corticosteroid- binding globulins Inhibitor of p450 enzymes Major use in the treatment of endometriosis Treatment of fibrocystic disease of the breast Hematologic or allergic disorders

CLOMIPHENE A partial estrogen agonist Ability to stimulate ovulation Incidence of multiple pregnancy is aproximately 10% Clomiphene may have not an adverse effect in pregnant woman Long treatment for more than a year may be associated with An increased risk for low-grade ovarian cancer;

Androgens Mechanism of action Effects Increased muscle mass Increased red blood cell production Maintain normal bone density Clinical use ANDROGEN REPLACEMENT THERAPY IN MEN GYNECOLOGIC DISORDERS USE AS PROTEIN ANABOLIC AGENTS ANABOLIC STEROID AND ANDROGEN ABUSE IN SPORTS Toxicity Masculinizing actions and are most noticeable in women Hepatic dysfunction, Cholestatic jaudice, elevation of liver enzymes Hepatocellular carcinoma

Androgens: Preparations available and relative androgenic: anabolic activity in animals. Androgenic: Anabolic Activity Testosterone1:1 Testosterone cypionate1:1 Testosterone enanthate1:1 Methyltestosterone1:1 Fluoxymesterone1:2 Oxymetholone1:3 Oxandrolone1:3-1:13 Nandrolone decanoate1:2.5-1:4

Antiandrogens Receptor inhibitors Flutamide Spironolactone 5-  -reducatase inhibitors Finastride Gonadotropin releasing hormone analogs Combined hormonal contraceptives Inhibitors of steroids synthesis

Control of androgen secretion and activity and some sites of action of antiandrogens

Finasteride An inhibitor of 5a-reductase Benign prostatic hyperplasia Hirsutism in women Early male pattern baldness in men

Flutamide A potent antiandrogen The treatment of prostatic carcinoma Occasionally causes mild reversible hepatic toxicity It frequently causes mild gynecomastia