Gonadal Hormones Pharmacology and Med Chem

Cholesterol

27 carbon structure

Testosterone

19 carbons

estradiol

21 carbons

progesterone

21 carbons

Progesterone

C21 natural occurring hormone

Medroxyprogesterone Acetate (MPA)

activity similar to progesterone

• Used with estrogens for MHT (menopausal hormone therapy)

Estranes

have both progesteronic and androgenic activities

Gonanes

less androgenic activity than estranes

• In oral and injectable contraceptives

Dihydrotestosterone, androstenedione

weak androgens

progestins

-progesterone

-medroxyprogesterone acetate

-estranes

-gonanes

male gonadal hormones

-testosterone

-Dihydrotestosterone, androstenedione

estrogens

Phenolic A ring is the principal feature responsible for selective

high-affinity binding to ER-alpha and ER-beta

estrogens

-estradiol

-estrone and estiol

-synthetic estrogens

estradiol

C18 major secretory product of ovary

estrone and estriol

mostly from liver and peripheral tissues

synthetic estrogens

ethinyl substitutions at C17 increase oral effectiveness by inhibiting first pass hepatic metabolism

• Women of reproductive age - ovary

• Postmenopausal women - principle source of circulating estrogen is adipose where estrone synthesized from dehydroepiandrosterone

• Men - estrogens produced by testis, but most extragonadal

• Local production by cell type (e.g. mammary tumors)

• Aromatization of androgens

• Hydrolysis of estrogen conjugates (sulphate and glucuronides)

• Placenta makes large amounts of estrone and estriol

What are the sources of estrogens in the body?

What is the role of estrogens

-Development (puberty, secondary sex characteristics)

-Neuroendocrine control of ovulation

-Cyclical prep of reproductive tract for fertilization and implantation

-Bone, spermatogenesis and behavior - males

-Bone Mass

• Decrease number and activity of osteoclasts (bone

resorption)

• Affect bone growth and epiphyseal closure both sexes

-Elevate serum triglyceride; reduce total serum cholesterol (slight)

• Alter bile composition by increasing cholesterol and decreasing bile acid secretion

• Gallstones in some receiving estrogen

-Increase both coagulation and fibrinolytic pathways

• Imbalance = adverse effects in some

What are the roles of estrogens?

seals epiphyseal plate too soon

If we know estrogens and androgens promote bone growth, why might their premature use result in shorter ultimate height?

Raloxifene

-is a selective estrogen receptor modulator

-Used in treatment for osteoporosis

it is an agonist in some tissues and an antagonist in others

What is the advantage of using a SERM for the premature use of estrogens and androgens that typically result in shorter ultimate height?

Estrogens - ADME

• In circulation bound to sex hormone-binding globulin = unavailable

• In liver estradiol converted to estrone, estriol, 2-hydroxy derivatives and phase 2 enzyme conjugates that are excreted in bile

• Bile metabolites can be reabsorbed from intestine = enterohepatic circulation

• Hepatic effects can be undesirable (e.g. increased synthesis of clotting factors) so use other routes of exposure (vaginal, transdermal, injection) to avoid first pass liver exposure [but still almost completely absorbed into circulation]

-primary hypogonadism

-menopausal hormone therapy

-contraception

What are the clinical uses of estrogens?

primary hypogonadism

At 11-13 years of age to stimulate puberty through 51 years of age

menopausal hormone therapy

• Hot flushes, sweating, insomnia, atrophic vaginitis relieved by

estrogens

• Use lowest dose possible for symptomatic relief

• Considerations: age, risks for cardiovascular disease, osteoporosis, breast or endometrial cancer

contraception

estrogens used in combo with progestins

AEs of estrogens

• Postmenopausal Uterine Bleeding

• Cancer (breast, endometrial)

• Nausea/headaches

• Breast tenderness

• Hyperpigmentation

• Cholestasis

• Gallbladder disease

• Hypertension

Selective Estrogen Receptor Modulators and Antiestrogens

• Ligands that change conformation of estrogen receptors and interactions with molecular coactivators/corepressors in cell and promoter-specific contexts to confer tissue-selective actions

• Competitively block estrogen from binding to ERs

beneficial estrogenic actions in some tissues (e.g. bone, brain, liver) while having antagonizing effects in breast and endometrium

What are the goals of selective estrogen receptor modulators and antiestrogens?

SERMS

Tamoxifen, Toremifene (breast cancer)

Raloxifene (osteoporosis, breast cancer)

antiestrogens

Clomiphene and Fulvestrant (pure antagonists in all tissues, infertility, breast cancer)

Progestins

-Natural - Progesterone

• Precursor to estrogens, androgens and adrenocortical steroids

• Synthesized in ovary, testis, adrenal cortex and placenta

-Synthetic Progestins - variable activities, largely oral

roles of progestins

• Neuroendocrine - Decrease frequency of GnRH pulses

• Estrogen + progesterone action on endometrium essential for normal menstrual pattern. Abrupt decline in progesterone = onset of menstruation

• During pregnancy progesterone suppresses menstruation and uterine contractility and with estrogen important in mammary gland development

• Metabolic effects (insulin, lipase etc) depending on progestin

Progestin ADME

• Rapidly absorbed by any route

• Almost completely metabolized by first pass; oral typically ineffective

• Excreted as glucuronic acid conjugate in urine

• Available as micronized oral formulation, oil for injection, vaginal gel, and IUD for contraception and vaginal insert for reproductive technology

• Ethinyl substituents slow hepatic metabolism

pregnancy termination, emergency contraception, induce labor, and to treat uterine leiomyomas, endometriosis, meningiomas, and breast cancer

Applications of Antiprogestins and Progesterone Receptor Modulators:

Mifepristone

is a competitive receptor antagonist for both progesterone

receptors. For termination of early pregnancy.

Ulipristal

-is a selective progesterone receptor modulator, partial agonist at

PRs.

-Inhibits ovulation when taken up to 5 days after intercourse

AEs of Combo Oral Contraceptives

-Cardiovascular

• Hypertension, Myocardial Infarction, Hemorrhagic or Ischemic Stroke, Venous Thrombosis and Embolism

• Minimized for nonsmokers without other risk factors

-Cancer

• Breast, Hepatocellular, Cervical

• Lower risk than previously thought

-Endocrine and Metabolic

• Complex

-Miscellaneous

• Headaches

• Break through bleeding

• Decreased bone mineral density (progesterone only in teens)

role of androgens

sperm maturation

androgens ADME

• Testosterone can not be taken orally - rapidly metabolized by liver

• Esterifying a fatty acid on the 17-hydroxyl group of testosterone makes it more lipophilic

• Testosterone can be delivered transdermally

• Alkylating the 17-hydroxyl group of testosterone reduces hepatic clearance, but less androgenic than testosterone and more hepatotoxic

Androgens clinical uses

• Androgen replacement therapy

• Gynecological disorders in women (often with estrogens)

• Anemia (rare now)

• Growth stimulators in boys with delayed puberty

• Anabolic steroid and androgen abuse in sports

• Aging men (not FDA approved)

Androgens AEs

-Masculization in women or children

-Excessive doses in men result in feminization

• Gynecomastia, testicular shrinkage, infertility

• Why do you think so???

-17 alkylated - hepatic dysfunction, increased bilirubin jaundice

-Acne

-Sleep apnea

-Azoospermia

Antiandrogens

• Since dihydrotestosterone—not testosterone—appears to be the essential androgen in the prostate, androgen effects in this and similar dihydrotestosterone-dependent tissues can be reduced by an inhibitor of 5α-reductase (e.g. Finasteride or Dutasteride)

• Flutamide is a potent antiandrogen that has been used in the treatment of prostatic carcinoma. Although not a steroid, it behaves like a competitive antagonist at the androgen receptor