UHH DNP PROGRAM Instructor: DR. AARON JACOBS 3 HOURS€¦ · ADVERSE EFFECTS • Nausea, GI upset...

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Sex Hormone Pharmacology

Instructor: DR. AARON JACOBS 3 HOURS

UHH DNP PROGRAM

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1. Hypothalamic-Pituitary-Reproduction Axis [GnRH, LH, FSH (and hCG)]

2. Sex Steroids 3. Fertility Agents 4. GnRH (LHRH) Agonists/Antagonists 5. Hormone Replacement Therapy 6. Selective Estrogen Receptor Modulators 7. Estrogen Receptor Antagonists 8. Aromatase Inhibitors 9. 5α-Reductase Inhibitors 10. Testosterone Antagonists 11. Contraception

Pharmacology: Sex Hormones Lecture Outline

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Anterior pituitary

Hypothalamus

GnRH portal blood

LH, FSH general circulation

Hypothalamic-Pituitary-Reproduction Axis Pharmacology: Sex Hormones

Sex Steroids, Reproduction

Gonads

Hypothalamic-Pituitary-Reproduction Axis

GnRH = Gonadotropin Releasing Hormone

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Pharmacology: Sex Hormones

Precursor sequence GnRH sequence

MKPIQKLLAGLILLTWCVEGCSSQHWSYGLRPGGKRDAENLIDSFQEIVKEVGQLAETQRFECTTHQPRSPLRDLKGALESLIEEETGQKKI

• 10 amino acid peptide • Synthesized in hypothalamus from precursor protein

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GnRH receptor (G-protein coupled)

Gαs AC

ATP cAMP

LH, FSH expression

Ca2+ Ca2+

GnRH Mechanism

AC = adenylate cyclase

LH, FSH release


GnRH

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LH = Luteinizing Hormone FSH = Follicle Stimulating Hormone


Glycoprotein hormone α-chain (shared)

β-chain (unique)

+

TSH (thyroid stimulating hormone) and hCG (human chorionic gonadotropin) are also α + β hormones


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LH Mechanism LH receptor (G-protein coupled)

Gαq

PIP2 (IP3 + DAG)

PLC PLC = phospholipase C

Steroid biosynthesis enzyme expression

Androgens


LH

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FSH receptor (G-protein coupled)

Gαs AC

ATP cAMP


Estrogen biosynthesis enzyme expression

SHBG expression

Androgens Estrogens

FSH Mechanism


FSH

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Leydig cells Sertoli cells

Spermatagonia Spermatids

Testes


Androgens


LH Leydig cells P450scc

3β-HSD 17β-HSD

FSH Sertoli cells SHBG

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Oocyte Antrum

Granulosa cells Theca cells

Ovarian follicle

LH Theca, Granulosa cells P450scc 3β-HSD 17β-HSD

Granulosa cells Aromatase SHBG

FSH

Androgens, Progesterone

Estrogens


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Cholesterol

Pregnenolone

17-OH-Pregnenolone

17α-OHase

Dehydroepiandrosterone (DHEA)

17,20-Lyase

Androstenediol

17α-OHase

17,20-Lyase

Dihydrotestosterone (DHT)

5α-reductase

Progesterone

17-OH-Progesterone

Androstenedione

Testosterone (T)

P450scc

17β-HSD 17β-HSD

3β-HSD

3β-HSD

3β-HSD

3β-HSD

RED = LH-induced enzymes


Estradiol (E2)


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Cholesterol

17-OH-Progesterone

Androstenedione

Pregnenolone

P450scc

Progesterone

3β-HSD

Theca Cell Granulosa Cell

Red = LH-Induced Green = FSH-Induced

Testosterone

17β-HSD

Estradiol

Aromatase

Aromatase

Estrone

17β-HSD

Estrogen Biosynthesis

Androstenedione


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Hypothalamus

Gonads

Anterior pituitary

Sex Steroids

Androgens Androgens Estradiol Progesterone

GnRH

LH, FSH


NEGATIVE FEEDBACK

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Sex Hormone Binding Globulin (SHBG)

Transcortin (aka CSBG) (corticosteroid-binding globulin)


Gonads, Liver

Estrogen, Thyroid hormone

SHBG

Insulin, IGF-1 (GH), Androgens

SHBG

Androgens Estrogens

Progesterone Aldosterone Cortisol

Low levels are a marker of: Diabetes (IR)

High levels can reduce testosterone, estrogen availability

Sex Steroids

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T

Target cells

AR

Gene Expression

SHBG

Lipophilic crosses membranes

T DHT

5α-reductase

AR AR


“Androgen Response Element”

H2N COOH Transcription

Activation DNA

Binding Ligand (T) Binding

Nuclear Receptors (e.g. AR, ER, PR)

DHT > T (3-fold)

Relative AR affinity

ANDROGENS

Sex Steroids

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Gene Expression

E2

ER

ER ER

E2 AKT

NF-κB

Cell Survival, Proliferation

Membrane E2 Receptor

Nuclear E2 Receptor

Target cells

“Estrogen Response Element”

E2

SHBG

E2 > Estrone > Estriol Relative ER affinity

ESTROGEN Lipophilic crosses membranes

Sex Steroids

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Gene Expression

P4

PR

PR PR

P4 Nuclear Receptor

Target cells

“Progesterone Response Element”

P4

CBG


PROGESTERONE Lipophilic crosses membranes

Sex Steroids

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90% of circulating T

Circulating T: 44% bound to SHBG 54% bound to albumin 1-2% free

Testosterone Sources Male: Testes + Adrenals Female: Ovaries + Adrenals = LEVELS 5-10 TIMES LESS than men

DHEA 5-10% of circulating T

peripheral conversion

DHEA-S (“pool”)

Pharmacology: Sex Hormones Sex Steroids

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Androgen Effects Growth

• Male sex characteristics (hair, • Muscle mass • Bone growth, maturation

CNS, Behavioral • Mental, physical energy • Increased libido • Social aggression?? (Wingfield, J.C., et al. (1990). Am. Nat. 136:829-846)

Cancer • Promotes growth of androgen-dependent cancers (CaP)


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DHEA-sulfate (300:1; DHEA-S:DHEA) Male AND Female: Adrenals (AGE-DEPENDENT)

mcg

/dl

DHEA

-S

DECADE OF LIFE DECADE OF LIFE

Range: HIGH LOW

Range: HIGH LOW


MALE DHEA-S RANGE FEMALE DHEA-S RANGE

Sex Steroids

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Estrogen Sources Female:

MAJOR sources: • Follicle • Corpus luteum • Placenta

MINOR sources: • Liver • Adrenals • Breasts


Male: • ALSO make estrogen • Male levels ~ postmenopausal female

Sex Steroids

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Estrogen Effects Growth

• Muscle growth • Bone growth • Bone resorption (promotes bone mineral retention) • Breast, endometrial, uterine growth

Vasculature • BP ( NO and Prostacyclin (PGI2) levels) = vasodilation • Risk of atherosclerosis (lipid profile: HDL LDL, in WOMEN) • Risk of DVT, PE (about 2-3x higher when on HRT) • Anti-inflammatory

Cancer • Promotes estrogen-dependent cancers (some breast cancer)

Sex Steroids

FEMALE HORMONE CYCLE Day: 0 7 14 21 28

FSH, Estradiol: • Promote growth of 10-20 primary follicles

LH Surge (Days 13-14): • Increases progesterone production • Promotes maturation of “dominant” follicle • Follicle wall rupture and oocyte release 23


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Progesterone Sources Female:

MAJOR (pregnancy) sources: • Corpus luteum (early) • Placenta (mid-late)

MINOR sources: • Liver • Adrenals • Breasts

Male: • Negligible


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Progesterone Effects Reproduction (Pregnancy Recognition)

• Breast, endometrial, uterine growth • Maternal immune response • Lactation • Uterine smooth muscle contraction • Body temperature (+0.5°C)


Implantation 5-10 ng/ml

Full term 100-200 ng/ml

Ovarian Progesterone

Placental Progesterone

Normal Mensus

Post-partum, Lactation 26


Progesterone: The pregnancy hormone

Sex Steroids

Anterior pituitary

LH surge (day 13-14)

Ovaries (LH Receptor)

Progesterone

Uterus Implantation

hCG (= placental LH)

Half-lives LH: 20 min hCG: 24 hr

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Progesterone

• Follicle Stimulating Hormone (FSH) • Human Menopausal Gonadotropins

• Menotropins • Urofollitropin

• Recombinant Follitropins (ALFA, BETA) • Chorionic Gonadotropin (hCG) • Lutropin ALFA • Clomiphene

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Fertility Agents Pharmacology: Sex Hormones

FSH injections (SQ, IM) 1-2 weeks

Ovarian stimulation

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FSH/hCG for fertility

follicle growth

hCG injection 1 day (HIGH dose)

Ovulation induction

ovulation

Fertility Agents

+ GnRH Antagonists

premature ovulation

LH (optional) LOW dose

Menotropins (Menopur®; Repronex®) = FSH + LH

• From post-menopausal urine • Mixture of hormones (includes LH + FSH) • Generally less potent than purified recombinant FSH

Human Menopausal Gonadotrpins (hMGs)

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Urofollitropin (Bravelle®) = “cleaned up” FSH • From post-menopausal urine • 98% of LH removed (using antibody capture) leaving mostly FSH

Pharmacology: Sex Hormones Fertility Agents

Follitropin-ALFA (Gonal-F®); Follitropin-BETA (Follistim®)

Bioreactor (large-scale cell culture production)

• Made in Bioreactors (CHO cells – genetically engineered) - Fast cell growth - High protein yield - N-glycosylation of recombinant proteins • Purified by antibody chromatography • ALFA = BETA (indistinguishable physical/bio properties)

Recombinant FSH

Chromatography Purified rFSH

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HALF-LIFE SQ (1 day); IM (2 days)

FSH (hMG or recombinant)

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CONTRAINDICATIONS • Primary ovary failure • Ovarian cysts or enlargement • Pregnant women (may cause fetal harm) • Cancer (b/c elevated hormone may promote growth!)

ADVERSE EFFECTS • Nausea, GI upset, Breast tenderness • Ovarian enlargement (abdominal pain) ~ 20% • Ovarian hyperstimulation syndrome (OHSS) ~ 10% • Multiple pregnancies (~10-20 %) • Thrombotic events (caused by elevated E2)

Fertility Agents

Chorionic Gonadotropin (hCG)

Recombinant Formulation (SQ) Ovidrel®

Choron 10®, Gonic®, Novarel®, Pregnyl®, Profasi® From urine of pregnant women

From Human Urine (IM)

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PHARMACOKINETICS • BIOAVAILABILITY: about 40% (SQ or IM formulations) • HALF-LIFE: 1-2 days

Fertility Agents

ADVERSE EFFECTS • Headache, irritability, restlessness, fatigue • Breast tenderness, enlargement • Ovarian enlargement • OHSS • Thrombotic events


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The Lancet (1954) 264(6845): 946-947

Regimen: • 3-4 weeks hCG SQ (or SL drops) • 500 calorie diet • hCG injection clinics/forums

Chorionic Gonadotropin (hCG) POTENTIAL MISUSE: Weight loss (Boxed warning: do not use for weight loss)

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Br. J. Clin. Pharmacol. (1995) 40(3):237-243 The effect of human chorionic gonadotropin (HCG) in the treatment of obesity by means of the Simeons therapy: a criteria-based meta-analysis. Lijesen GK, Theeuwen I, Assendelft WJ, Van Der Wal G. S. Afr. Med. J. (1990) 77(4):185-189 Human chorionic gonadotrophin and weight loss. A double-blind, placebo-controlled trial. Bosch B, Venter I, Stewart RI, Bertram SR West. J. Med. (1977) 127:461-463 Human Chorionic Gonadotropin (HCG) in the treatment of obesity. Greenway FL, Bray GA JAMA (1976) 236(22):2495-2497 Chorionic gonadotropin in weight control. A double-blind crossover study. Young RL, Fuchs RJ, Woltjen MJ Am. J. Clin. Nutr. (1976) 29:940-948 Ineffectiveness of human chorionic gonadotropin in weight reduction: a double-blind study. Stein MR, Julis ME, Peck CC, Hinshaw W, Sawicki JE, JJ Deller Jr Am. J. Clin. Nutr. (1963) 12:230-234 Chorionic gonadotropin in the treatment of obese women. Craig LS, Ray RE, Waxler, SH, Madigan H

Scientific studies uniformly reject hCG for weight loss

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Misuse: Body building

Androgens

• Testicular atrophy • Gynecomastia

Hypothalamus

GnRH

Anterior pituitary

FSH, LH

Testes

Anabolic Steroids

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Androgens

hCG

Fertility Agents

Lutropin ALFA (Luveris®) – approved 2004

Recombinant Luteinizing Hormone Used to help promote follicle development in women with very low LH release. (NOT FOR INDUCTION) PHARMACOKINETICS Administration: SQ Drug absorption << elimination This allows use as drug even though The SERUM half life of LH is only 20 min The net BIOLOGICAL half-life is 18 hr SIDE EFFECTS Similar side-effects to hCG

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Clomiphene (Clomid®)

E2 Receptor Degradation

LESS E2 negative feedback • GnRH release • FSH/LH release

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Drug Class = Selective Estrogen Receptor Modulator (SERM)

Mechanism of action:

+ clomiphene

Fertility Agents

Hypothalamus

Anterior pituitary

GnRH

FSH, LH

Ovaries Estradiol

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Clomiphene

Clomiphene


PHARMACOKINETICS • MIX of stereoisomers

62% E (LOW potent, FAST metabolism) 38% Z (MORE potent, SLOW metabolism) Z = ‘active component’

• Metabolism (Z): SLOW metabolism (hepatic, CYP2D6) • Half-life (Z): 5-7 days • Excretion: feces

ADVERSE EFFECTS • Bloating, Hot Flashes • Enlarged ovaries • OHSS

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Clomiphene (Clomid®)

Fertility Agents

LHRH Agonists • Leuprolide (Eligard®, Lupron®) - INJ • Histrelin (Supprelin®, Vantas™) - INJ • Goserelin (Zoladex®) - INJ • Triptorelin (Trelstar®) - INJ • Nafarelin (Synarel®) - NASAL

LHRH Antagonists • Cetrorelix (Cetrotide®) - INJ • Ganirelix - INJ • Degarelix (Firmagon®) - INJ

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GnRH (LHRH) Agonists/Antagonists Pharmacology: Sex Hormones

Examples of Use (AGONISTS) • Androgen-dependent CaP • Estrogen-dependent breast cancer • Endometriosis • Uterine Fibroids • Precocious Puberty

Examples of Use (ANTAGONISTS)

• Controlled Ovulation (fertility – slide 29) Cetrorelix, Ganirelix

• Hormone-sensitive cancer (CaP) Degarelix

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Pharmacology: Sex Hormones GnRH (LHRH) Agonists/Antagonists

• Pulsatile GnRH: LH and FSH • Continuous GnRH: LH and FSH secretion

Experiment perfomed on Oopharectomized female monkey

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AGONISTS MIMIC CONTINUOUS GnRH NET EFFECT: INHIBIT LH and FSH


Hypothalamus GnRH

Anterior pituitary

LHRH Agonist

AGONISTS: Initial LH/FSH Surge (1-2 weeks)

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LH, FSH Gonads

Sex Steroids

GnRH (LHRH) Agonists/Antagonists

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Hypothalamus GnRH (LHRH)

Anterior pituitary

LHRH Agonist

AGONISTS: followed by Desensitization


LH, FSH

Gonads

Sex Steroids


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Hypothalamus GnRH

Anterior pituitary

LH, FSH

Gonads

Sex Steroids

LHRH Antagonist

ANTAGONISTS: Direct inhibition


ADVERSE EFFECTS AGONISTS:

• Tumor flare (transient) Initial rise in steroid levels causes WORSENING of symptoms (inflammation, bone pain, fatigue)

ANTAGONISTS: (Degarelix) NO TUMOR FLARE BOTH:

• Hot-flashes, Nausea, etc. • Decreased bone density (decreased E2)

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Pharmacology: Sex Hormones Hormone Replacement Therapy

normal cycle

Estradiol Progesterone

Hypothalamus

Anterior pituitary

GnRH

FSH, LH

Changes in female hormone levels WITH AGE

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Unconjugated Estradiol (non-sulfate form) (Alora®, Climara®, Delestrogen®, Elestrin®, Estrace®, Estraderm®, Menostar®, Vivelle®, etc.)

Estradiol forms available, incl.: • Acetate • Cypionate • Hemihydrate salt • Valerate

Esterified estrogens (Menest®) Na+ salts of Estrone sulfate + Equilin sulfate

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Natural (USP) (mare’s urine)

Conjugated estrogens, equine (Premarin®)

MAIN COMPONENTS: (Na+ salts of) • Estrone sulfate (52-61%) • Equilin sulfate (22-30%) • 17α-Dihydroequilin sulfate (13-19% ) • 17α-Estradiol sulfate (2-9%) • 17β-Dihydroequilin sulfate (0.5-4%)

+ TRACE LEVELS OF: • Equilenin sulfate • 17α-Dihydroequilenin sulfate • 17β-Dihydroequilenin sulfate • δ8,9-Dehydroestrone sulfate • 17β-Estradiol sulfate

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Conjugated estrogens, synthetic

Synthetic estrogens “B” (Enjuvia™) SYNTHETIC mixture of ALL 10 estrogens (as sulfates) found in mare’s urine

Synthetic estrogens “A” (Cenestin®) = Enjuvia™ minus δ8,9-Dehydroestrone sulfate

Synthetic

APPROVALS for HRT in MENOPAUSE • Treat Vasomotor Symptoms • Prevent Osteoperosis

OTHER estrogen uses • Female hypoestrogenism (hypogonadism, ovarian failure) • Uterine bleeding caused by hormone imbalance • Atrophic vaginitis • Cancers: certain advanced breast and prostate

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FORMULATION (depends on intended use)

• Topical emulsion • Tablets • Transdermal • Injections

Common ADVERSE EFFECTS • Dizziness, headache • Abdominal cramps, bloating

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Serious ADVERSE EFFECTS • Breast cancer • Endometrial cancer (if used “un-opposed” without P4) • DVT, PE, Stroke, MI • Dementia

Hormone Replacement Therapy

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CONTRAINDICATIONS • Vaginal bleeding • History of DVT, PE, Stroke, MI • Estrogen-dependent CANCER

except in select advanced metastatic disease • LIVER DISEASE • PORPHYRIA (high blood porphyrin levels)

WHY? BECAUSE E2 INHIBITS uroporphyrinogen decarboxylase

• PREGNANCY


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What is the connection with Cancer?

STEPS: 1. Estradiol hydroxylation by CYP1B1 – to 4-hydroxy-estradiol 2. DNA adduction by 4-OH-E2 (on guanine bases) 3. Mutation (mistakes during proofreading or DNA synthesis) 4. Cancer INITIATION (due to mutations)

Tumor INITIATION


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What is the connection with Cancer?

Cell Division (S-phase)

ERα E2 P P

Rb P P

Retinoblastoma (Rb)

CycD1 CDK4/6

Cyclin dependent kinases (CDK) 4, 6

CycD1

Cyclin D1

E2

membrane receptor

nuclear receptor

Cell Survival

Tumor PROMOTION


Endometrium

“UN-OPPOSED” = estrogen only

ERα

Mutation, Proliferation

Estrogen

PRB

Differentiation (growth arrest)

Progesterone

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CANCER RISK

CANCER RISK

Combination therapy (if uterus is intact) Conjugated Estrogens (CE): 25 days on / 5 days off + Medroxyprogesterone Acetate (MPA): 2 weeks on, rest off

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PROTECTS AGAINST UTERINE CANCER

Monotherapy (If uterus removed, i.e. hysterectomy) Conjugated Estrogens (CE) only


Women's Health Initiative (WHI) – 1992-2002

27,347 women 50-79 y.o.

Estrogen + Progestin vs. Control DATA NOT SORTED BY AGE • 41% ↑ Stroke • 29% ↑ MI • 50% ↑ DVT • 26% ↑ Breast cancer

NHLBI STOPPED trial 2002 (3 years premature)

JAMA (2002) 288(3):321-33

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Uterus Intact

Hysterectomy

16,608 (E + P)

10,739 (E)

• 37% ↓ Colorectal cancer • 33% ↓ Hip fracture • 24% ↓ Total fracture


Pro-coagulation factors Fibrolytic factors

HRT is a “mixed-bag” ELEVATED risk for stroke

Beneficial lipid profile NO production (vasodilation) Endothelial healing Reactive oxygen species (ROS) Endothelial inflammation / Death

DECREASED risk for CHD

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Pro-coagulation factors Fibrolytic factors

Clotting effects are REDUCED by SLOW-RELEASE formulation Transdermal: (Estraderm®, Climara®, Vivelle-Dot®, Menostar®)

DOSE-RELATED effect of estrogen

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How to reduce stroke risk?


2008 findings imply: • Risk is AGE-DEPENDENT • Some aspects “reversed” from 2002 findings!

“Since the original publication of the WHI E+P trial in 2002, an extensive collection of data have been published in piecemeal fashion, contributing to the confusion and misperception of the effects of HT on risks and benefits.”

Estrogen only cohort

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Diethylstilbestrol (DES)

1941: HRT 1947: Prevention of miscarriage (5-10 million) 1960s: Adjuvant for breast and prostate cancer

1971: Linked to vaginal, cervical cancer in offspring 1975: Use prohibited in pregnant women 1997: Discontinued as drug in US - citing cardiovasular risk

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soybean joke:

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Enterolactone Secoisolariciresinol

Lignans

Flax seed


Phytoestrogens

Daidzien Genistein

Isoflavinoids

Soybean Kudzu


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Genistein from soy extract is marketed as Femarelle® HRT alternative for post- menopausal women


Scientific ‘value’? 25 women, before/after 8 weeks treatment compare to WHI (>10,000 women)

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Have MIXED PRO- and/or ANTI-estrogenic actions Vary depending on (a) drug, (b) target tissue

SERM USES: Fertility:

• Clomiphene (Clomid®; Serophene®)

Osteoporosis: • Raloxifene (Evista®) osteoporosis lecture

Breast Cancer: • Tamoxifen (Nolvadex®, Valodex®) • Toremifene (Fareston®)

Pharmacology: Sex Hormones Selective Estrogen Receptor Modulators

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(gene expression) DNA

binding Hormone binding

AF-1 (A/B) AF-2 (E)

Mechanism of Action (1) ER AGONIST Estrogen Receptor

Estradiol

Gene expression

RNApol

SERM

Gene expression

RNApol


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(gene expression) DNA

binding Hormone binding

AF-1 (A/B) AF-2 (E)

Mechanism of Action (2) ER ANTAGONIST Estrogen Receptor

Estradiol

Gene expression

RNApol

SERM

NCor1

SMRT

NO Gene expression


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Mechanism of Action (3) ER Degradation*

+ SERM Receptor degradation

* For Clomiphene, this is thought to be the principal mechanism of action


PHARMACOKINETICS • Administration: ORAL • Absorption: FOOD DOUBLES ABSORPTION • Protein binding: High (90%) • Metabolism: Hepatic (CYP2D6 + CYP3A4) • Serum Half-life: 10 h • Excretion: feces (69%); urine (24%)

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Tamoxifen Selective Estrogen Receptor Modulators

ACTIONS • Bone: AGONIST (Bone retention) • Endometrium: PARTIAL AGONIST (Promotes growth) • Breast: ANTAGONIST (Inhibits breast cancer growth)

Tamoxifen Long t1/2

N-desmethyltamoxifen Long t1/2

4-hydroxytamoxifen High affinity

Short t1/2

Endoxifen Highest affinity

(100X tamoxifen) Short t1/2

CYP2D6 CYP2D6

CYP3A4

CYP3A4

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Tamoxifen METABOLIC ACTIVATION

Selective Estrogen Receptor Modulators

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Tamoxifen Long t1/2

4-hydroxytamoxifen High affinity

Short t1/2

CYP2D6

N-desmethyltamoxifen Long t1/2

Endoxifen Highest affinity

(100X tamoxifen) Short t1/2

CYP2D6

Tamoxifen

2D6 INHIBITORS

2D6 INDUCERS


METABOLIC ACTIVATION


2D6 Inhibitors (Strong) Bupropion Fluoxetine Paroxitene Quinidine 2D6 Inducers (Strong)

Dexamethasone Rifampin Glutethimide

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Poor 2D6 Metabolizers 7% Caucasians 3% Blacks <1% Asian/Pacific

Tamoxifen ACTIVATION = drug low efficacy

Tamoxifen ELIMINATION = drug low efficacy


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DRUG INTERACTIONS

• Tamoxifen can Warfarin (avoid combination!)

• Tamoxifen is a P-glycoprotein inhibitor Can interfere with the absorption, elimination of P-glycoprotein substrates, or reduce efficacy of certain chemotherapeutics


Tamoxifen Selective Estrogen Receptor Modulators

Common ADVERSE EFFECTS • Hot Flashes (i.e. vasomotor effects) • Amenorrhea

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Tamoxifen

Data from National Surgical Adjuvant Breast and Bowel Project (NSABP), 1998

Endometrial adenocarcinoma DVT, PE

Breast cancer (incidence and mortality)

Other effects of tamoxifen


Toremifene (Fareston®)

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USES • Metastatic breast cancer • Off-label: Mastalgia (breast pain), Prostate cancer


PHARMACOKINETICS • Administration: ORAL • Protein binding: High (>99%) • Metabolism: Hepatic • Half-life: 5 days • Excretion: metabolites in feces (90%)


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ADVERSE EFFECTS • Hot flashes, diaphoresis • Nausea • Liver toxicity • QTc-prolonging effects of other drugs

Toremifene


Fulvestrant (Faslodex®) USES:

• Metastatic breast cancer • Off-label: uterine bleeding

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COMPARISON to Tamoxifen: • Solely an ANTAGONIST on all ER-expressing tissues • Sometimes arrests growth of tamoxifen-resistant cancers • Second-line agent (in tamoxifen resistance)

• Does NOT stimulate uterine growth (tamoxifen does) • Fewer vasomotor effects (hot-flashes)

Pharmacology: Sex Hormones Estrogen Receptor Antagonists

ADVERSE EFFECTS Most common: Hot Flashes, Nausea, Fatigue Less common: Headache, Back pain, GI distress

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Fulvestrant

PHARMACOKINETICS • Administration: IM • Protein binding: High > 99% • Metabolism: Extensive hepatic • Half-life: 40 days • Excretion: metabolites in feces (>90%)

Pharmacology: Sex Hormones Estrogen Receptor Antagonists

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• Aminoglutethimide (Cytadren®) adrenal lecture • Testolactone (Teslac®) second-line agent

• Anastrozole (Arimidex®) • Letrozole (Femara®) • Exemestane (Aromasin®)

Pharmacology: Sex Hormones Aromatase Inhibitors

USES: Breast and prostate cancers (steroid-responsive cancers)

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PHARMACOKINETICS: Anastrozole, Letrozole:

• Administration: ORAL • Absorption: rapid, complete • Bioavailability: 90-100% • Half-life: 2-3 days • Excretion: feces (Anastrazole); urine (Letrozole)

Exemestane • Administration: ORAL • Absorption: rapid, incomplete ( with fats) • Bioavailability: 40% • Half-life: 1 day • Excretion: feces + urine


ADVERSE EFFECTS • Hot flashes, Flushing • Edema, Hypertension • Nausea • Decreased BMD, High cholesterol (recommended: monitoring of BMD, cholesterol)

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P450 INHIBITION PROFILES • Anastrozole: none • Letrozole: CYP2A6 inhibitor • Exemestane: none

Aromatase Inhibitors

METABOLISM: • Anastrozole: extensive hepatic

(N-dealkylation + hydroxylation) • Letrozole: hepatic, various P450s • Exemestane: mainly CYP3A4

(means you need to the dose if taking 3A4 inducers)

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MECHANISM: • Anastrozole, Letrozole = COMPETITIVE INHIBITOR • Exemestane = SUICIDE (non-competitive) INHIBITOR

Forms reactive “quinone methide” This forms fovalent adduction to aromatase aka “aromatase inactivator”


Type I 5α-reductase

Type II 5α-reductase

Skin, Liver

Testicles Prostate Hair follicles

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Pharmacology: Sex Hormones 5α-Reductase Inhibitors

Finasteride (Proscar®, Propecia®)

1/3 of DHT

T

2/3 of DHT

T

Dutasteride (Avodart®)

Finasteride • Male pattern baldness (Propecia) • Benign prostatic hyperplasia (Proscar) – NOT CaP! • Prostate Cancer Chemoprevention (in BPH)

25% reduction CaP over 7 years

Dutasteride • Benign prostatic hyperplasia (Avodart) – NOT CaP! • Prostate Cancer Chemoprevention (in BPH)

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ADVERSE EFFECT: Sexual dysfunction


PHARMACOKINETICS (main differences in color)

Finasteride Dutasteride • Admin: ORAL • Bioavail: 60% • Vd: 76 L • log P: 3.03 (LESS hydrophobic) • Metabolism: CYP3A4 Metabolites not very active • Half-life: 6 h • Excretion: feces, urine

• Admin: ORAL • Bioavail: 60% • Vd: 300-500 L • log P: 5.09 (MORE hydrophobic) • Metabolism: Hepatic (CYP3A4) Active metabolite: 6-hydroxydutasteride • Half-life: 5 wk • Excretion: feces, urine

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Flutamide

Bicalutamide (Casodex®) Nilutamide (Nilandron®) • Metastatic prostate cancer

• Often combined with LHRH agonist • Off-label: (Flutamide)

Female hirsutism due to Polycystic ovary disease

USES

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PHARMACOKINETICS • Administration: ORAL • Absorption: Rapid, complete • Half-lives:

Flutamide: 6 hr Nilutamide: 2-4 days Bicalutamide: 6 days

Pharmacology: Sex Hormones Testosterone Antagonists

Most Common ADVERSE EFFECTS

• Hot flashes • Edema, hypertension • GI distress, nausea • Dyspnea (shortness of breath)

Some effects may be attributed to the LHRH agonist

(used in combination w/LHRH agonist)

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BOXED WARNING Flutamide may cause liver failure

Pharmacology: Sex Hormones Testosterone Antagonists

Enovid Progestin: Norethynodrel 5 or 10 mg Estrogen Component: Mestranol 75 mcg

1957 – approved for menstrual irregularity 1960 – approved for birth control

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Pharmacology: Sex Hormones Hormonal Contraception

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Hypothalamus

Gonads

Anterior pituitary

Sex Steroids Folicle Development

Sustained Estradiol + Progesterone

GnRH

FSH/LH

Mechanism:

Ovulation

Follicular Luteal Menses


Combination pill (monophasic)

(1960)

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20-days on

5-days off

Follicular Luteal


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Sequential pill (1965-1976)

20-days on

5-days off

Ovulation

Follicular Luteal Menses

Triphasic pill (1984) (e.g. Ortho-tri-cyclin) Estrophasic pill (2001) – (Estrostep) Estrogen “stepped” but Progestin constant

7-days (dummy pills)

Biphasic pill (1982)

10 days 11 days

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ESTROGENIC COMPONENT

Ethinylestradiol (EE) Most common component

Mestranol Found in few preparations:

• Ortho-Novum 1/50 • Norinyl 1/50

• Oral Bioavailability: 40% • Protein binding: high (98%) • Metabolism: Hepatic (CYP3A4) • Half-life elimination: 24 hours • Excretion: Urine and feces

PHARMACOKINETICS (EE)

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Main Mechanism: Constant E2 inhibits LH, FSH surges ( OVULATION)

Estradiol (E2) – valerate salt LOW (1-5%) Bioavailability – NEED high, mg quantities!

Relative POTENCY*

Progesterone

Ethynodiol diacetate

Desogestrel

Gestodene

*as measured by inhibition of ovulation, compiled from different sources (not all agents used clinically in U.S.)

= Stongly Androgenic

= Mildly Androgenic

Medroxyprogesterone acetate (MPA)

= Anabolic

L-Norgestrel

Norgestrel

Norethindrone, Norethindrone acetate

PROGESTATIONAL COMPONENT

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USES • Hormonal contraception • Acne (Ortho Tri-Cyclen®, Estrostep®) • Premenstrual dysphoric disorder (PMDD) (YAZ®)

Symptoms: Mood disorders: despair, irritability, anxiety, mood swings CNS: headaches, fatigue, hunger, sleep disorders Other: bloating, palpitations, breast tenderness

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ELEVATED RISK: • Thromboembolism • Stroke • MI • Liver tumor • Gallbladder disease • Visual disturbances • Fetal abnormalities • Hypertension

Common ADVERSE EFFECTS • Nausea • Chloasma/Melasma (dark patches on skin) • Breakthrough bleeding • Breast tenderness, enlargement

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Boxed Warning: NO smoking!


PROGESTIN-ONLY ORAL Contraceptives “Mini-pill” or POP

Norethindrone most preparations

Norgestrel (Orvette®)

NO break in dosage (not-cycled) NO menses NO DVT, MI NOT contraindicated in sickle-cell patients (NO clotting risks of estrogen pills)

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Main Mechanism: Viscosity of cervical MUCOUS Secondary Mechanisms:

• Ovulation (ONLY AT HIGH DOSES) e.g. Cerazette® • Implantation • Motility of uterine tubes (fertilization)

PROGESTIN-ONLY DEPOTS (Depo-Provera®, Depo-subQ Provera®)

Medroxyprogesterone acetate (MPA)

• Amenorrhea • Abnormal uterine bleeding • Endometriosis, Endometrial carcinoma • HRT

Non-contraception uses for MPA:

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Diethylstilbestrol (never approved, used off-label 1960’s-70’s)

“Morning after pill”

Preven-EC™ (1998-2004) (aka Yuzpe Regimen) E-Estradiol + L-Norgestrel

Plan B® (approved 1999) Non-prescription 2006 L-Norgestrel

• Nausea, vomiting, cramps • Headache, dizziness • Menstrual irregularities • Breast tenderness

Adverse Effects

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Pharmacology: Sex Hormones Emergency Contraception

Main Mechanism: Prevents OVULATION Secondary Mechanism: Inhibits IMPLANTATION

Mifepristone (RU-486) MECHANISM OF ACTION

• PROGESTERONE ANTAGONIST • Primary effect: Decay, shedding of

endometrial tissue + embryo • Given along with misoprostol (prostaglandin analog)

to myometrial contractions – expel tissue PHARMACOKINETICS

• Administration: ORAL • Absorption: rapid • Protein binding: 98% • Metabolism: CYP3A4 • Bioavailability: 70% • Excretion: feces

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Pharmacology: Sex Hormones Abortifacient

ADVERSE EFFECTS • Nausea, vomiting, cramps • Headache, dizziness

UHH DNP PROGRAM Instructor: DR. AARON JACOBS 3 HOURS€¦ · ADVERSE EFFECTS • Nausea, GI upset...

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Transcript of UHH DNP PROGRAM Instructor: DR. AARON JACOBS 3 HOURS€¦ · ADVERSE EFFECTS • Nausea, GI upset...