The Gonadal Hormones & Inhibitors

Dr. Meera Ababnneh, Pharm.D, PhD

Compounds with estrogenic activity

Commonly used estrogens.

Average Replacement Dosage
Ethinyl estradiol Micronized estradiol Estradiol cypionate Estradiol valerate Estropipate Oral 0.005-0.02 mg/d 1-2 mg/d 2-5 mg every 3-4 weeks 2-20 mg every other week 1.25-2.5 mg/d 0.3-1.25 mg/d

Conjugated, esterified, or mixed estrogenic substances:

Injectable
Transdermal Quinestrol Chlorotrianisene

0.2-2 mg/d
Patch 0.1-0.2 mg/week 12-25 mg/d

Methallenestril

3-9 mg/d

OVARIAN HORMONES
Estrogens 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

OVARIAN HORMONES
Progestins
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

The usual routes of administration and durations of action of the synthetic progestins(1)
Activities1
Route Duration of Action Estrogenic Androgeni c Antiestrogenic Antiandrogenic Anabolic

Progesterone and derivatives Progesterone Hydroxyprogesterone caproate Medroxyprogesterone acetate Megestrol acetate IM IM 1 day 8-14 days Tabs: 1-3 days; injection: 412 weeks 1-3 days sl sl + -

IM, PO PO

17-Ethinyl testosterone derivatives Dimethisterone PO 1-3 days sl -

The usual routes of administration and durations of action of the synthetic progestins(2)
Activities1

Route

Duration of Action

Estrogenic

Androgenic

Antiestrogenic

Antiandrogenic

Anabolic

19-Nortestosterone derivatives Desogestrel Norethynodrel2 Lynestrenol3 Norethindrone2 Norethindrone acetate2 Ethynodiol diacetate2 L-Norgestrel2 PO PO PO PO PO PO PO 1-3 days 1-3 days 1-3 days 1-3 days 1-3 days 1-3 days 1-3 days + + sl sl sl + + + + + + + + + + + + +

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.

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

Some oral and implantable contraceptive agents in use

Estrogen (mg) Monophasic combination tablets Alesse, Aviane, Lessinea, Levlite Biphasic combination tablets Ortho-Novum 10/11, Necon 10/11 Ethinyl estradiol 0.02 L-Norgestrel 0.1 Progestin (mg)

Days 1-10
Days 11-21 Triphasic combination tablets Enpresse, Triphasil, Tri-Levlen, Trivora Days 1-6 Days 7-11 Days 12-21 Daily progestin tablets

Ethinyl estradiol
Ethinyl estradiol

0.035
0.035

Norethindrone
Norethindrone

0.5
1.0

Ethinyl estradiol Ethinyl estradiol Ethinyl estradiol

0.03 0.04 0.03

L-Norgestrel L-Norgestrel L-Norgestrel

0.05 0.07 5 0.12 5

0.0
Ovrette Implantable progestin preparation Norplant System
L-Norgestrel (six tubes of 36 mg each)

D,L-Norgestrel

7 5

Anitsteogens and antiprogestins

Selective estrogen receptor modulators (SERMs)
Tamoxifen Raloxifen Clomiphen

Antiprogestins
mifepristone

Synthesis inhibitors
Aromatase inhibitors: anastrazole, exemestane Danazol

Pure estrogen receptor antagonists

Fulvestrant

Gonadotropin releasing hormone analogs

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
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 Testosterone Testosterone cypionate Testosterone enanthate Methyltestosterone Fluoxymesterone Oxymetholone Oxandrolone Nandrolone decanoate 1:1 1:1 1:1 1:1 1:2 1:3 1:3-1:13 1:2.5-1:4

Antiandrogens
Receptor inhibitors
Flutamide Spironolactone

5--reducatase inhibitors
Finastride

Gonadotropin releasing hormone analogs Combined hormonal contraceptives Inhibitors of steroids synthesis

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

Agents That Affect Bone Mineral Homeostasis

Hormonal regulators of bone mineral homestasis

PTH Vitamin D Calicitonin Estrogens Glucocorticoids

Bone mineral homeostasis

The hormonal interactions controlling bone mineral homeostasis

The hormonal interactions controlling bone mineral homeostasis

Vitamin D and its major metabolites and analogs

Chemical and Generic Names Abbreviation

Vitamin D3; cholecalciferol

Vitamin D2; ergocalciferol 25-Hydroxyvitamin D3; calcifediol 1,25-Dihydroxyvitamin D3; calcitriol 24,25-Dihydroxyvitamin D3; secalcifediol Dihydrotachysterol

D3
D2 25(OH)D3 1,25(OH)2D3 24,25(OH)2D3 DHT

Calcipotriene (calcipotriol)
1-Hydroxyvitamin D2; doxercalciferol 19-nor-1,25-Dihydroxyvitamin D2; paricalcitol

None
1(OH)D2 19-nor-

Conversion of 7-dehydrocholesterol to vitamin D3 and metabolism

Actions of Parathyroid Hormone (PTH), Vitamin D, and FGF23 on Gut, Bone, and Kidney

Intestine

PTH Increased calcium and phosphate absorption (by increased 1,25[OH]2D production)

Vitamin D Increased calcium and phosphate absorption by 1,25 (OH)2D

FGF23 Decreased calcium and phosphate absorption by decreased 1,25(OH)2 production

Kidney

Decreased calcium excretion, increased phosphate excretion

Calcium and phosphate Increased phosphate excretion may be decreased excretion by 25(OH)D and 1,25(OH)2D1
Increased calcium and Decreased mineralization phosphate resorption by due to hypophosphatemia 1,25(OH)2D; bone formation may be increased by 1,25(OH)2D and 24,25(OH)2D

Bone

Calcium and phosphate resorption increased by high doses. Low doses may increase bone formation.

Net effect on serum levels

Serum calcium increased, serum phosphate decreased

Serum calcium and phosphate both increased

Decreased serum phosphate

Secondary Hormonal Regulators of Bone Mineral Homeostasis

Calcitonin Glucocorticoids Estrogens

Nonhormonal agents
Bisphosphonates Calcimimetics Thiazides Fluoride Other drugs
Gallium nitrate Plicamycin Strontium Ranelate

Typical changes in bone mineral density with time after the onset of menopause