Estrogens, Progestins and Androgens

Becky Worthylakebworth@lsuhsc.edu

Outline

• Overview

• Estrogens – General

• Estrogens & Modifiers – Therapeutic Formulations & Uses

• Progestins – Therapeutic Formulations & Uses

• Contraception

• Androgens – General

• Androgens – Uses & Therapeutic Formulations

Hypothalamus (GnRH)& Pitutary

Luteinizing Hormone &Follicle Stimulating Hormone

Ovaries & Testes

Reproduction

Overview: Endocrine Physiology

Overview: Molecular Mechanisms

Overview: Molecular Mechanisms

Outline

• Estrogens – General

• Synthesis

• Physiology

• Regulation

Cholesterol

Pregnenolone

Estradiol

OH

OH

OH

A B

C D1

2

3

45

6

7

89

10

CH 3

1119

12

13

1415

1617

18CH 3

CH 2CH 3CH

CH 2

CH 2 CH 2

CH 3

CH 32021

23

2224

25

27

28

Testosterone

DHEA

Androstenedione

Progesterone

Androstenedione

aromatase

Synthesis

Growth of

Epithelium

rate of bone

skin structure

Liver synthesis of

follilcleGrowth of endometrium

Lowers Plasma cholesterol

Behavioral effects

ESTROGENS

Reproductive Tissues

Vaginal Mammary Gland

Decreases

resorption

Increases blood coagulability Maintains normal

Reduces Bowel motility

Sperm transport

Transport Proteins

Ovarian

Non-reproductive Tissues

Physiology

1. Estrogen exerts both negative and positive feedback.

2. Gonadal hormones act on both the anterior pituitary and the hypotalamus.

TAKE HOME POINTS:

3. Higher brian centers influence the release of GnRH from the hypothalamic neurons

STRESS

visual

HYPOTHALAMUS

GnRH

GonadotrophsLH, FSH

LongLoop

LongLoopLH

FSH

pinealolfactory

Estrogen

Estrogen(+/-)

Progesterone ovary

LongLoop

Estrogen(+/-)

FSH, LHSame aDifferent b

Regulation: Feeback Loops

-12 -10-8 -6 -4 -2 0 2 4 6 8 1012 14MensesMenses

Menses

Ovulation

Follicular Growth Corpus Luteum

48

1216202428323640

60

80

LH

and

FSH

(m

U/m

l )

Prog Estradiol

10

8

67

9

54321

1.00.90.80.70.60.50.40.30.20.1

(ng / ml)P

E

E

FSH

F

LHRegulation : Circulating Levels

0 4 8 12 16 20 24 28 32Days

Plas

ma

Leve

lEstradiol

ProgesteroneOvulation

oF

Basal BodyTemperature

Cervical MucusElasticity

Vaginal Cornification

Endometrium

Glycogen Vacuoles

Menses MensesProliferative Phase

SecretoryPhase

Follicular LutealRegulation: Impact on Reproductive Tissues

Outline

• Estrogens & Estrogen Modifiers – Therapeutic Formulations and Uses

• Therapeutic Estrogens

• SERMs (selective estrogen receptor modulators)

• Estrogen Synthesis Inhibitors

Therapeutic Estrogens

Indications• Primary Hypogonadism• Postmenopausal Hormonal Therapy• Oral Contraceptives • Suppress ovulation in patients with intractable dysmenorrhea or hirsutism• Fertility treatments

DRUG COMMENTS

Estradiol Main estrogen in premenopausal women. Poor oral bioavailability

Effective as a patch (ESTRADERM, ESTROGEL)

Intramuscular delivery sustains release for weeks (DEPO ESTRADIOL)

Topical administration with vaginal cream (ESTRING)

Ethinyl-estradiol Semi-synthetic: commonly used on oral contraceptives

Estrone Natural estrogen-main ingredient of conjugated estrogens (PREMARIN)

Side effects Nausea, fluid retention, breakthrough bleeding, change in menstrual flow, breast tenderness.

Adverse Effects: Thrombolytic complications; endometrial carcinoma; breast carcinoma; and hypertension. In men - feminization of genitalia & impotence.

Contraindications: Pregnancy, incomplete bone growth, undiagnosed genital bleeding; stroke, thrombophlebitis, or thromboembolic disease., heart disease. Women with family history of breast or uterine cancer (BRCA gene)

Drug Interactions: efficacy of oral anticoagulants and hypoglycemic agents

adverse effects of tricyclic antidepressants

the effects of oxytocin on the uterus.

St. John's wort may cause loss of contraceptive or hormonal-replacement efficacy of estrogens

Therapeutic Estrogens Cont’

Uses: HRT – Symptoms of Menopause

LH, FSH

Estrone is major Estrogen

GnR

H

Normal, Midcycle

Normal

Postmenopausal

GnR

H

Hot FlashesHDL/LDL ratio

(Increased risk of MI and stroke, especially in the first year)

Uses : HRT – Effects of Treatment

Early HRT used estrogen alone: increased risk of uterine (endometrial) cancer. As a result, addition of progestins is now used to limit endometrial hyperplasia

Medroxyprogesterone (MPA) acetate is most commonly used

• Various regimens are used: estrogen for 25 days with inclusion of MPA during last 10-13 days of estrogen, 5-6 days with no hormones

• Combination formulations: PREMPRO (PREMARIN plus MPA) given at fixed dose daily; PREMPHASE (PREMARIN for 28 days and MPA for days 14-28)

• Newer combos of estrogens with progestins: FEM HRT (estradiol plus norethindrone acetate)ORTH PREFEST (estradiol plus norgestimate)

• Vaginal creams (PREMARIN) or a ring device (ESTRING) can be used instead of oral doses . Reduces vaginal dryness, yeast infections and urinary tract infections.

Uses: HRT - Formulations

SERMs (Selective Estrogen Receptor Modulators)

• Selectivity is possible because• ER-a and/or ER-b show differential tissue expression. • Conformation dependent binding to DNA and transcription factors • Tissue dependent responses ranging between pro-estrogenic, partially

estrogenic and anti-estrogenic effects

SERMs: Tamoxifen – Breast Cancer

2-3 fold increased risk of deep vein thrombosis & pulmonary embolism

- Most effective in treatment of tumors that are ER-positive (50% response) or ER + PR positive (70-80% response rates). Responses of ER-negative tumors is < 10%.

- Adjuvant therapy with chemo or radiation in treatment

- Preventative agent for women at high risk for breast cancer.

- Resistance is usually developed in 5 years, which may, in part, reflect alterations in the ER receptors in the tumors.

SERMs: Tamoxifen continued

Raloxifene (EVISTA):

- High affinity for both ER-a and ER-b- Treatment of osteoporosis in post-menopausal women.- Does not cause proliferation of the endometrium or breast tumor cells

Side effects: 2-3 fold risk of deep vein thrombosis and pulmonary embolism

Interactions: Ampicillin absorption Raloxifene warfarin efficacy

SERMs: Other

• Clomiphene Weak agonist and strong antagonist for ER-a or ER-b.

- Oppose the negative feedback effects of endogenous estrogen. amplitude of the LH and FSH pulses

- Major use: induction of ovulation in women with an intact hypothalamic-pituitary-ovarian axis

- Adverse effects: multiple births, ovarian cysts

• ICI 182,870 Fulvestrant (FASLODEX) - pure estrogen antogonist - effective in treating tamoxifen-resistant tumors

Anti-Estrogens

• Steroidal: exemestane (AROMASIN)

• Non-steroidal: anastrozole (ARIMIDEX), letrozole (FEMARA)

- Specifically block the local production of estrogens in hormonally-responsive tissues.

- Second-line treatment for breast cancer in patients whom tamoxifen therapy is unsuccessful, but new studies rapidly proving its efficacy and promoting earlier use

- Aromatase inhibitors do not have the bone protecting activity of tamoxifen, and adjuvant therapies to prevent bone loss are in trials

Estrogen Synthesis Inhibitors

• Progestins – Therapeutic Formulations & Uses

• Therapeutic Progestins

• anti-Progesterones

Outline

• Naturally occurring progesterone (low oral bioavailability)

- Micronized particles suspended in oil and packaged in gelatin capsules (PROMETRIUM) - Vaginal gel (CRINONE) - Slow-release intrauterine device (PROGESTASERT) • 17-a-hydroxy-progesterone derivatives have substitutions at C17 that slow hepatic

metabolism : medroxyprogesterone (MPA) (PROVERA)

• 19-nor testosterone derivatives display primarily progestational rather than androgenic activity : norethindrone

• Replacement of the 13-methyl group of norethindrone with a 13-ethyl substituent are more potent progestins and less androgenic: norgestrel, nomegestrol

Progestins – Therapeutic Progesterone

Mechanism of Action: Interacts with PR to mimic the stimulatory affects of progesterone

Physiological Target: Reproductive Tract- Decreases estrogen-driven endometrial proliferation - Establishment and maintenance of pregnancy

Common Uses:

- Oral contraceptives

- HRT to limit estrogen’s effects on the endometrium

- Uterine Bleeding disorders - Premature labor (decrease uterine contractions) - Stimulate Appetite in AIDS or cancer patients

Progestins continued

Progestins: anti-Progesterones

Mifepristone (RU 486) (mifeprex): PR antagonist

Used in first trimester to terminate pregnancy (along with prostaglandins to increase uterine contractions)

Post-coital contraceptive (prevent implantation)

Investigational: induction of labor after fetal death and treatment of endometriosis.

Adverse Effects: vaginal bleeding, abdominal pain and cramping

Contraindicated in patients with vaginal bleeding, adrenal dysfunction or asthma (due to anti-glucocorticoid actions)

Interactions: Decreases efficacy of anticoagulants.Inhibits hepatic metabolism by CYP3A4 (eg.anti-retroviral protease inhibitors, calcium-channel blockers, carbamazepine)

Outline

• Contraception

• Therapeutic Estrogens & Progesterones

• Oral Contraceptive Formulations

• Emergency Contraception

• Extended-Regimen Contraception

• Mechanism of Action

• Effects

Hypothalamus

Pituitary

Ovary

Uterus

Cervix and Vagina

LH FSH

GnRHOral ContraceptivesGnRH analogs

Fallopian Tube

ovum EstradiolProgesterone

Sperm transport

Ovum transport

Implantation

Tubal Ligation

IUDProgestin only contraceptive

Barrier MethodsNatural family planning

Contraception

Oral Contraceptives: History

• 1950: Pincus et al (progesterone prevents ovulation)• 1959: 1st pill appeared in USA• 1960: mini pill (progesterone alone)• 1970: Introduction low dose or second generation of OCS• 1980: biphasic or triphasic regimens• 1990: 3rd generation OCs

e.g, norgestimate 0.25mg or desogestrel 0.15 mg)

Contraception: Therapeutic Estrogens1. Estrogens: mestranol and ethinyl estradiol

Hepatic Metabolism

• Absorbed efficiently in GI tract. Mestranol is biologically inactive and must be metabolized to ethinyl estradiol. Peak plasma levels within 1 hr after oral administration

• Clearance is ~ 60% 24 hr after oral dose

• Ethinyl estradiol is 2X more potent than mestranol

OH

O

HH

H

19-NORTESTOSTERONE

OHC CH

O

HH

H

NORETHINDRONE

OC CH

O

HH

H

ETHYNODIOL DIACETATE

AC

AC

Contraception: Therapuetic Progestins• 19-NOR Steroids :Progestins

Removal of 19-carbon changed major hormonal effect from an androgen to progestin while maintaining oral activity

• Estranes: have some androgenic activity as well as estrogenic/anti- estrogenic actions. Rapidly absorbed (Norethindrone)

OHCH2 C CH

O

H3C

HH

H

DESOGESTREL

OCOCH3CH2 C CH

HON

H3C

HH

H

NORGESTIMATE

OHCH2 C CH

O

H3C

HH

H

NORGESTREL

H2C

• Gonanes: More potent than estranes and less androgenic activity and are now used in the 3rd generation combination oral contraceptives

(Norgestrel, Norgestimate, Desogestrel)

Contraception: Therapuetic Progestins cont’

• 1st generation: products containing mestranol

• Low dose OCs: products containing < 50 mcg ethinyl estradiol

• 2nd generation “Low-Dose” : products containing gonanes (levonorgestrel, norgestimate) and other members of norethindrone family and 20, 30, or 35 mcg ethinyl estradiol

• 3rd generation: desogestrel or gestodene (new progestins) with 20, 30, or 35 mcg ethinyl estradiol

Therapeutic Estrogen & Progestin Combinations

Monophasic:

The concentrations of estrogens and progestins are fixed in the pill, which is taken for 21 days followed by 7 days of “hormone-free” pills.

a. mestranol (50 µg) + norethindrone (1.0 mg) (ORTHO-NOVUM 1/50, NORINYL 1+50)

b. ethinyl estradiol (20-30 µg) + a progestin (estranes or the gonanes, 0.15-1.5 mg). Include ORTHO-NOVUM 1/35, NORDETTE, ORTHO-CEPT , LOESTRIN)

Contraception: Formulations

• ethinyl estradiol (fixed concentration) + norethindrone (lower concentration in the first 7-10 days and then higher concentration for the next 11-14 days). (Include ORTHO-NOVUM 10/11, JENEST-28)

• The rationale is to limit exposure to the higher concentration of the progestin.

Biphasics:

Contraception: Formulations

• Fixed concentration of ethinyl estradiol with 3 different concentrations of norethindrone

(TRI-NORINYL ORTHO-NOVUM 7/7/7),

• Fixed concentration of ethinyl estradiol with three concentrations of gonanes.

(ORTHO-TRI-CYCLEN - norgestimate; TRI-LEVLEN, TRIPHASIL - levonorgestral ).

• Rationale is to mimic the hormonal changes in the menstrual cycle

Triphasic:

Contraception: Formulations

• Oral formulations of norethindrone (micronor) or levonorgestrel (ovrette) taken daily

• Subdermal implants of levonorgestrel (norplant) for slow-release and long-term contraceptive actions (up to five years)

• IM injections of medroxyprogesterone (depo-provera) that provides effective contraception for 3 months

• IUD that releases low amounts of progesterone locally (progestasert).

Contraception: Formulations

Progestin Only:

• Drugs used for the prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure.

• Emergency hormone contraceptive regimens are highly effective and decrease the risk of pregnancy by 75 percent

• To be effective these must be taken within 72 hours of intercourse

• May also inhibit ovulation or fertilization depending on timing of administration Alteration of the endometrium, sperm penetration, and tubal motility are also affected . ESTABLISHED PREGNANCIES ARE NOT HARMED.

• Two products are available:– Plan B: 0.75 mg levonorgestrel– Preven: 0.25 mg levonorgestrel and 0.05 mg ethinyl estradiol (this product

includes a pregnancy test kit)

Emergency Contraceptives

Advantages • Period once every 3 months• Period last about 3 days with decreased bleeding ,

Side Effects: Breakthrough bleeding and spotting

Levonorgestrel / ethinyl estradiol 0.15 mg / 0.03 mgAnd either placebo or ethinyl estradiol tablets 0.01 mg tablets) Brand Names: Jolessa, Quasense, Seasonale, Seasonique

91-day courses of tablets

Seasonique: incorporates low-dose estrogen rather than placebo tablets in an effort to limit bloating, hormonal fluctuations, and breakthrough bleeding.

Extended Regimen Contraception

Contraceptives: MOA

LH/FSH release

Follicular development & ovulation

SPERM Transport

EGG Transport

Progestin only:• Thick cervical mucus• Implantation of blastocyst in endometrium• Contractions of uterus & F.tubes are modified

Contraceptives: MOA

• Start First day of next menstrual period

• Some suggest starting on first Sunday following onset of menses– Usually avoids menstrual period on weekends– Most clinicians recommend backup for at least 2 cycles

Initiating Method

Other Beneficial effects

1. Decreases Dysmenorrhea2. Decreases benign breast and ovarian cysts3. Regulates cycle in anovulatory women4. Decreased blood loss during menstruation5. 50% reduction in ovarian and endometrial cancer.

Effects: Benefits

Drugs that disrupt liver metabolism and increase oral contraceptive metabolism

- anti-seizure medications, St. John’s wort- antibiotics tetracycline and ampicillin- HIV protease inhibitors- Anti-tuberculosis drugs such as rifampin

Oral contraceptives effect the activity of other drugs

a. anticoagulantsb. benzodiazepines, c. beta-blockersd. corticosteroids, and tricyclic antidepressants

Effects: Drug Interactions

1. Absolute

a. History of thromboembolism, MI, strokeb. Impaired liver functionc. Known or suspected breast cancerd. Undiagnosed abnormal vaginal bleedinge. Known or suspected pregnancy f. Smokers over age 35 (may use progestin-only)

2. Relative

a. – Migraine headachesb. – Hypertension - ok if <35, or healthy, or BP controlledc. – Elective surgery: Discontinue 4wks. prior to major surgeryd. – Gallstones/ Cholecystitise. – Epilepsy: anti-seizure meds may decrease effectiveness of OCP’sf. – Diabetes: small risk or worsening vascular disease.

Effects: Contraindications

Outline

• Androgens – General

• Synthesis

• Regulation

• Physiological Effects

CHOLESTEROL

Pregnenolone

Progesterone Dehydroepiandrosterone(DHEA)

Testosterone

P450sccNADPH

FSHAromatase5a-Reductase

EstradiolDihydrotestosterone(DHT)

LH

Androgens : Synthesis

Androgens : Regulation

Plasma Testosterone

5 a-reductase

conjugating enzymes

Testosteronetestes, pituitary, muscle

Estradiol fat, liver, CNS, skin, hair

17 b-dehydrogenase

Conjugatesliver, kidney

17 ketosteroidsliver, kidney

Excretory Metabolites

Dihydrotestosteroneprostate, scrotum, penis, bone

Biologically Active

aromatase

*Circulating testosteroe and dihydrotestosterone1-2 % - free65% - bound to SSBG -- (sex steroid binding

globulin)33-34% - bound to albumin

* Only free and loosely bound albumin fractions of testosterone are biologically active. SSBG- may serve as a circulating reservoir for androgens.

Androgens : Regulation

• Circulating testosterone and dihydrotestosterone

1-2% Free65% bound to SSBG (sex steroid binding globulin)33-34% bound to albumin

Testosterone

DHTLarynx

VLDL

HDL

LDL

DHT

DHT

E2Beard Growth

Prostate

Penis

Puberty FetalEpididymusVas deferens

Seminal vesicles

ExternalGenitalia

E

Muscle UpperBodyFat

Ephyiseal Closure

Sperm Production

ADULT

DHT

E

Increased

PIT(-)

Sperm Production

Sex drivebehavior

DHT

E

Androgens : Physiology

Outline

• Androgens – Uses & Therapeutics

• Treatable Conditions

• Therapeutic Formulations of Testosterones and Androgens

• Androgen Antagonists

A. Male hypogonadism: develop or maintain secondary sex characteristics

B. Andropause

C. Prostate Cancer

D. Male Pattern Baldness

Treatable Conditions

Condition: Adult Male Hypogonadism

Symptoms• Decreased libido• Erectile dysfunction• Infertility• Fatigue, weakness• Depression, loss of motivation,

irritability• Vasomotor phenomena

Signs• Decreased body hair• Decreased muscle mass• Small prostate and testes• Gynecomastia• Osteoporosis• Anemia

Treatment

Transdermal testosterone estersMonitoring for both beneficial and deleterious effects required, age dependent

Condition: Andropause• Changes are slower and more subtle: progressive decline (total and free) in

testosterone levels Leydig cell number and activity. • ~ 60% of healthy men over 65 have lower testosterone compared to 20-35 year

old men and may be related to impotence

Treatment:

• Pharmacological doses of testosterone in men muscle mass and muscle strength especially in combination with exercise. Also cognition and sense of well being.

• Negative Effects: Lipid profiles (LDL), prostate size, uninary symptoms

• New Developments: “STRM” selctive androgen recepotor modulators: Goal is to have anabolic effect on muscle mass and anti-androgenic effect on the prostate

• 17-a-alkylated androgens: decreased breakdown by liver, • but can elicit hepatic toxicity

Testosterone derivatives

Testosterone (HISTERONE) • oral admin. leads to absorption into the hepatic circulation

and rapid catabolism • Effective in transdermal patches

Theraputic Formulations: Testosterones

17aHydroxyl Group Esters• More lipophilic than testosterone• Converted to testosterone in the circulation

Testosterone enanthate (Delatestryl®)• Given IM once every two weeks

Testosterone undecanoate (Andriol®)• Absorbed into lymphatic system when

taken orally (40 mg capsules)

Testosterone propionate (Neo-Hombreol®)• Short duration of action (i.e. 1-2 days) even when

delivered IM

Theraputic Formulations: Androgens

17a Alkylated Testosterone• Hepatic metabolism retarded• Reduced androgenicity• Somewhat hepatotoxic

Methyltestosterone (Metandren®)• Taken orally (e.g. 10-50 mg/day in men, 5-25 mg/day for 4-6 months in

children)

Theraputic Formulations: Androgens

Potential Side Effects of Excessive Androgen Treatment

• Reduced spermatogenesis and fertility due to feedback inhibition of LH and FSH secretion from anterior pituitary

• Acne, particularly in women due to androgen stimulation of sebaceous glands beneath skin

• Virilization (including facial hair and hirsutism) in women and children

• In older men, increased risk of benign prostate hyperplasia and prostate cancer

• Hepatotoxicity (for 17a-alkylated androgens)

Theraputic Formulations: Side Effects

Anabolic Steroid and Androgen Abuse in Sports 100-200 x normal daily production in men

Androgen Receptor antagonists

Flutamide (EVLEXIN) and Bicalutamide (CASODEX). Bicalutamide has much less hepatoxicity

Used in conjunction with GnRH analogs to treat metastatic prostate cancer

Treat Hirsutism in women (due to hepatoxicity should not use for cosmetic purposes)

5-a-reductase inhibitors

Finasteride (PROSCAR) used to treat benign prostatic hypertrophy and male patterned baldness (PROPECIA)

Androgen Antagonists