Pharmacology of Estrogens and Progestins

December 15, 2015

Carol L. Beck, Pharm.D., PhD

The lecturer has no conflicts of interest related to this topic.

Educational Goals

• To understand how the structure and function of the estrogen and progesterone receptors affects drug actions and tissue specificity.

• To know the mechanism of action of: mifepristone, misoprostol, tamoxifen, raloxifene, fulvestrant, ulipristal. Know contraindications for their use.

• To know how estrogens and progesterones are used in contraception, menstrual cycle control, and hormone replacement therapy.

I. Estrogen and ProgesteroneRemember:

Estrogens and ANDROGENS (testosterone) are the Sex Steroids

•Bound by Sex Steroid Binding Globulin (SSBG)

Progesterone and Cortisol

•Bound by Transcortin aka Corticosteroid Binding Globulin

Only free drug/ hormone available to bind to receptors and produce response….

I. Estrogen and Progesterone

• Steroid structure– Steroids are lipids with three 6-C rings and

one 5-C ring– Five classes of steroid hormones

• Estrogens• Prostagens• Androgens• Mineralocorticoids• Glucocorticoids

STEROIDAL* ESTROGEN PROGESTERONE

Progestin +Luteo-sterone

Progesterone*Yes, there are non-steroidal estrogens

Combined Name

Structure

Metabolism/ Inactivation

• Inactivated by conjugation to sulfate esters or glucuronic acids– Metabolism of estrogen occurs in

peripheral tissue

• Metabolism is by oxidation– primarily in liver

• Excreted in urine

C. Biosynthesis 1. Progesterone

• Ovary (primarily corpus luteum) makes cholesterol progesterone

-During pregnancy, placenta also produces progesterone

Other sources:• Testis makes cholesterol progesterone• Adrenal makes cholesterol progesterone

ProgesteroneProgesterone (natural progestin): Additional info:• Produced by corpus luteum of the ovaries and the

placenta during 2nd half of menstrual cycle

(males– testes)– Also synthesized by adrenal cortex (male, female)– Promotes development of a secretory endometrium for

implantation of newly forming embryo– If no pregnancy, release from corpus luteum ends abruptly, and

this decrease stimulates onset of menses

• If conception, progesterone levels continue to support the endometrium and also inhibit future ovulation by suppressing LH.

2. Biosynthesis of EstrogenProducted by the Ovaries* (primarily follicular

phase—1st half-- but also by the corpus luteum) -makes estradiol which is converted to estriol and estrone

Liver makes estradiol which is converted to estriol and estrone

Peripheral tissue (adipose tissue) makes androstendione which is converted to estradiol estriol and estrone

* Primary source of sex hormones for women between puberty and menopause.

Biosynthesis of Estrogen

Estrogen• Suppresses FSH– so no dominant follicle, (no

ovulation)

3. Metabolism• Can occur in peripheral tissue, in which

androsteindione is converted to estrone

4. Estrogen: Protein Binding• 95% of estrogens circulate attached to

proteins, primarily sex hormone binding globulin (SHBG) and albumin. – ~5% is free/unbound

• SHBG has low capacity for binding but high affinity, albumin has high capacity but low affinity.

• Decreased SHBG leads to increased unbound circulating estrogens and androgens.

5. Neuroendocrine Regulation of Steroid Production

• Hypothalamic secretion of GnRH acts on pituitary to release gonadotropins (FSH and LH)

• Anterior Pituitary produces FSH (follicle stimulating hormone) and LH (luteinizing hormone) which act on the ovary and testis to stimulate steroid synthesis and gamete development.– FSH and LH on Ovary: Estrogen, Progesterone– LH on Testis: Testosterone (androgen)

Hypothalamus

Anterior

(Progesterone)

D. Pharmacodynamics1. Molecular Mechanism of Steroid Action

• Steroid hormones dissociate from binding protein and enter most cells by diffusion

• In target cells (i.e., cells sensitive to hormone), the steroid binds to receptors located in the cytoplasm and/or the nucleus (AKA “nuclear receptors”)

• Steroid receptor is activated by hormone (ligand); dimerizes; binds DNA; induces transcription.

More later about Estrogen and Progesterone receptors!

E. Female reproductive system

The menstrual cycle depends on a complex interaction between hypothalamus, pituitary, ovaries, and endometrium.

F. Systemic Effects of EstrogenFemale

1. Anabolic: Female Maturation– Development of vagina, uterus and tubes– Development of secondary sex

characteristics– Pubertal growth spurt

F. Systemic Effects of Estrogen

2. Blood Chemistry– Reduces plasma cholesterol– Increases HDL and decreases LDL

3. Suppresses cellular immune responses

4. Increases coagulation factors (increased coagulability) by:

antithrombin III plasminogen, II, VII, IX, X

F. Systemic Effects of Estrogen5. Bone

– Decrease rate of bone resorption by decreasing osteoclast activity

6. Reproductive system– Regulation of menstrual cycle– Proliferation of uterine and vaginal epithelium– Stimulates production of cervical mucus,

making it less viscous

7. Endrocrine: Increase thyroxine

Physiologic Effects of Estrogen – Menstrual Cycle

F. Systemic Effects of EstrogenMale

1. Stimulates growth of stromal cells in prostate

2. Essential for spermatogenesis

G. Systemic Effects of Progesterone

1. Blood chemistry HDL LDL

2. Reproductive system, female– Regulation of menstrual cycle– Modulates secretory differentiation and increases

vascularity in uterus– Maintains pregnancy– Represses uterine contractions (smooth muscle

relaxant)

G. Systemic Effects of Progesterone

SUMMARY: Menstrual cycle regulation:

• Induces secretory change in the endometrium

• At high doses suppresses gonadotropin release and suppresses ovulation

Physiologic Effects of Progesterone – Menstrual Cycle

Other Systemic Effects of Progesterone

Endocrine:• Increase basal insulin levels• Increase insulin response to glucose• Increase ketogenesis

Other:• Increase body temperature• Increase breathing response to CO2• Depressant/hypnotic effect on the brain

II. Clinical Uses of Steroid Hormones and their Antagonists

Estrogens as Therapeutic Agents

1. Can be naturally derived or synthetic

2. Most often PO, but also by vaginal, intranasal, IM, IV, and transdermal routes

3. Menstrual cycle control, ovulation induction, hormone replacement therapy

Progestagens as Therapeutic Agents

1. Prophylaxis against endometrial hyperplasia or carcinoma in estrogen-treated women

2. In some cases, appropriate for solo use:– Induction of withdrawal bleeding in amenorrhea– Contraception– Inhibition of gonadotropin secretion– precocious

puberty or treatment of endometriosis

Clinical Uses of Exogenous Hormones*

Contraception

Infertility treatment

Menopausal Management

Labor and Delivery

*To be discussed primarily in other lectures

A. Oral Contraception• Most oral contraceptives (OC) consist of a

synthetic estrogen and a synthetic progestin.– Synthetic hormones because natural are rapidly

inactivated when given PO

• OC differ in estrogen dose and dose/nature of progestin

• Combination OC prevent ovulation by inhibiting gonadotropin release via feedback to the hypothalamus and pituitary

A. Oral Contraception

• Clinical pharmacology of contraception lecture will discuss the side effects, toxicities, and selection of most appropriate OC for specific patients

Mechanism of Action: Combination Hormonal Contraception

Comgination OC prevent ovulation by inhibiting gonadotropin secretion through effects on the hypothalamus and pituitary.– Progestin– suppresses LH secretion; – Estrogen– suppresses FSH secretion

Adverse Effects:Combination Hormonal Contraception

A detailed discussion of adverse effects and indications and contraindications will be part of Dr. Lackritz’s lecture.

Drug Interactions:Combination Hormonal Contraception

MANY!! Remember, hepatic metabolism….(consequences of decreased metabolism? Increased metabolism?)

Structure

• Estrogens used in oral contraceptive agents are ethinyl estradiol and mestranol.

• Synthetic progestins in oral contraceptives in the United States include: – norethindrone, norethindrone acetate, ethynodiol

diacetate, norgestrel levonorgestrel, desogestrel, drospirenone, and norgestimate.

Mechanism of Action: Combination Hormonal Contraception

Act in central nervous system and reproductive organs.

CNS: acts on the hypothalamus and pituitary to prevent mid-cycle surge of luteinizing hormone (LH) and prevents ovulation.

Reproductive: • causes glandular atrophy in endometrium• inhibits implantation of the blastocyst• causes the formation of a thick cervical mucus

that inhibits sperm motility and migration.

Pharmacokinetics• Mestranol and ethinyl estradiol are

absorbed efficiently in GI tract; up to 60% excreted in urine after 24 h.– Can be absorbed transdermally and

transvaginally.

• Mestranol is an inactive prodrug– must be converted in liver to estrone/estriol

• Progesterone metabolism– liver, more than 30 metabolites identified.

B. Other routes of contraceptive administration

• Vaginal rings– NuvaRing

• Transdermal contraceptive patches– OrthoEvra

Progestin-only

• Long-activing injectable (Depo-Provera)

• Sub-dermal implants (Implanon)

C. Emergency Contraception

Efficacy - 75 % reduction in pregnancy rate; potential prevention of 1.7 million unplanned pregnancies per year in U.S.

Mechanism - Delay or inhibition of ovulation; possible inhibition of implantation

C. Emergency Contraception(covered in more detail by Dr. Lackritz)

1. Plan B (Levonorgestrol 0.75 mg)

(Progesterone) or

2. Ella (Ulipristal acetate 30 mg)

3. Other regimens:

Preven (levonorgestrel 0.25mg and ethinyl estradiol 0.05 mg)

Any OC at adequate doses

Insertion of an IUD within 72 hours

2. Ulipristal

Partial agonist/ partial antagonist at progesterone receptor

MOA: Binds to Progesterone receptor; prevents ovulation and prevents fertilized egg from attaching to the uterus

D. Medical Abortion• An abortion option for the first 49–63 days of

pregnancy• Most common regimen consists of:

– An oral dose of mifepristone which blocks the receptors of progesterone

– Followed by a dose of misoprostol (prostaglandin analogue) which causes the uterus to contract and empty

• Alternate regimen:– Methotrexate followed by misoprostol

E. Menstrual Cycle Control• For severe menorrhagia/ dysmenorrhea and

cannot tolerate OC

– Progesterone (Medroxyprogesterone)

– GnRH analogs such as Leuprolide– feed back to pituitary and cause initial increase in LH/FSH secretion followed by decrease to menopausal levels. (Patients will develop symptoms of menopause.)

F. Hormone Replacement Therapy for postmenopausal women

The controversy: increased risks of MI, stroke, breast cancer, pulmonary emboli, deep venous thrombosis in post-menopausal women treated with estrogens and progesterone during a 5 year study.

(should there have been additional subsets of the data? Helpful in some; harmful in others?)

Because of these risks, HRT should be prescribed at the lowest effective doses and for the shortest duration consistent with the treatment goals and risks for the individual woman.

Hormone Replacement Therapy

FDA –approved indications

a. treatment of moderate to severe vasomotor symptoms

b. treatment of moderate to severe atrophic vaginitis

c. prevention of postmenopausal osteoporosis, NOT treatment

Hormone Replacement Therapy-- Estrogens

• Natural estrogens include estrone, estradiol, and conjugated equine estrogens.

• Synthetic estrogens • Estrogens are most often administered by

mouth, but they can also be administered effectively by vaginal, intranasal, intramuscular, intravenous, and transdermal routes.

Rational for Progestion Use in HRT

• Prophylaxis against endometrial hyperplasia or carcinoma in estrogen treated women– Adding progestin attenuates endometrial

cancer risk

• Continuous combined, continuous sequential– both are used.

Hormone Replacement Therapy

Guiding Principles for ET/EPT therapy

a. Lowest effective dose

b. Shortest duration required

c. Type/route/regimen of E and P

d Individualized risks and benefits

e Patient satisfaction with therapy

Hormone Replacement Therapy

Contraindications to ET/EPT

a. Hormone-sensitive cancer

b. Unexplained uterine bleeding

c. Active liver disease (esp. with oral ET)

d. History of DVT/PE

e. Confirmed CVD

Hormone Replacement Therapy

Common side effects of ET/EPT

a. Uterine bleeding

b. Breast tenderness

c. Nausea/Abdominal bloating

III. Drugs acting on Estrogen and Progesterone Receptors

A. Review of Estrogen and Progesterone Receptor Physiology

1. Estrogen receptors: alpha and beta

•Different genes on different chromosomes

•Different tissue/cell distribution

•Different affinity for ligands

•Different genes activated

A. Review of Estrogen and Progesterone Receptor Physiology

2. Ligands for Estrogen receptors

•Estrogens: estradiol

•SERMS: tamoxifen, faloxifene, toremifene

•Novel ER-alpha and ER-beta selective ligands

A. Review of Estrogen and Progesterone Receptor Physiology

3. Receptor activity

•ER in many body tissues

•ER-Alpha and ER-beta levels depend on tissue

•ER-Alpha: reproductive system

•ER-beta: bone, brain, urinary tract

•Estradiol binds to both alpha and beta

•SERMS designed to be selective

Progesterone Receptors

1. Progesterone receptors: alpha and beta

– Different transcriptional activities– Cell type and promoter specific effects–

often PR-beta > PR alpha– PR alpha can repress PR beta and ER

signaling

B. ER/PR Pharmacology/ Pharmacodynamics

• In uterus PR opposes ER stimulation

• In breast PR increases ER stimulation

ER/PR Pharmacology/ Pharmacodynamics

Ligands can be

•Agonists

•SERMs/SPRMs

•Antagonists

ER/PR Pharmacology/ Pharmacodynamics

• Different ligands induce different receptor confirmations that determine response

• Partner proteins/ co-regulators

Many interrelationships between ER and PR pathways

• Progestins modulate estrogen action BUT also act independently

• Progestin effects on estrogen action vary in different tissues.

C. SERMs & Antagonists SERDs

• Selective Estrogen Receptor Modulator

• Mixed estrogen receptor agonist and antagonist, effect depends on tissue type

DRUGS THAT BLOCK ER ACTIVATION AND FUNCTION ARE ANTIESTROGENS

• SERMS: Tamoxifen, Raloxifene

• SERD: Fulvestrant

SERMs & Antagonists SERDs

1. Current hypothesis to explain the antiestrogen effects in different tissues:

a. protein conformation

b. co-activators for ER

c. alternate response elements

2. Tamoxifen (a SERM)• Tamoxifen (Nolvadex)

– Estrogen antagonist effect centrally and on breast tissue

– Estrogen agonist on uterus and coagulation profile

– Therapeutic Uses: metastatic breast cancer, prophylaxis

– Adverse Effects: hot flashes, vaginal bleeding, endometrial hyperplasia

– Contraindications: Hx DVT, PE, coagulopathy

– Pharmacogenetics…..

3. Raloxifene (a SERM)• Raloxifene (Evista)

– Estrogen antagonist centrally and on uterus and breast tissue

– Estrogen agonist on bone, lipids and coagulation profile

– Indications: postmenopausal osteoporosis, breast cancer prophylaxis

– Contraindications: Hx DVT, PE, coagulopathy

– Increase hot flashes– Warnings: NOT for pre-menopausal

women; incr. incidence DVT/PE

4. Fulvestrant (a SERD)

• Fulvestrant (Faslodex)

– Estrogen antagonist on breast; competes with estradiol

– Down regulates estrogen receptor protein in breast cancer

– Indications: metastatic breast cancer

D. Selective PR modulators (SPRMs) and Antagonists

1. Ulipristal (Ella)

SPRM

Emergency contraception

Take within 120 hours of unprotected intercourse or contraceptive failure (vs. 72 hours for other EC)

D. Selective PR modulators (SPRMs) and Antagonists

2. Mifepristone (Mifeprex, RU-486)

PR antagonist

Antagonist at glucocorticoid receptors

Restricted access

Pharm to Watch for…..

More….

•SERMS

•Selective PR modulators (SPRMs) and Antagonists

That’s all!

Get some rest over the break!

Handsome Blake, demonstrating the Greyhound TechniqueTM of resting.