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