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denucci@gdenucci.com

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Medicamentos atuantes no sistema reprodutivo feminino - Anticoncepcionais

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www.gdenucci.com

Dúvidas

denucci@gdenucci.com

Arquivo

Medicamentos atuantes no sistema reprodutivo feminino - Anticoncepcionais

Site

www.gdenucci.com

Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig 54-1

The anatomy of the female internal genitalia and accessory sex organs

Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig 54-1

The anatomy of the female internal genitalia and accessory sex organs

Ovarian cycle

Rupture of mature follice and release of

ovum (ovulatory phase)

Corpus luteum formation

(luteal phase)

Growth and development of the

follice (follicular phase)

Corpus luteum degeneration

Foyes Principles of Medicinal Chemistry – Fig. 29.2

800

600

400

200

0800

600

400

200

0

8

6

4

2

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Est

radi

ol (

pg/m

l)F

SH

and

LH

(n

g/m

l)

Days of female sexual cycle

FSH

LHEs

trad

iol

Ovu

lati

onO

vula

tion

Progesterone

Pro

gest

eron

e (n

g/m

l)

Men

stru

atio

n

Approximate plasma concentrations of the gonadotropins and ovarian hormones during the normal female sexual cycle

Guyton & Hall – Textbook of Medical Physiology – fig 81.3

Pu

ber

ty

Men

opau

se400

300

200

100

00-----12 13------40 50 60

Age (yr)

Est

roge

ns

excr

eted

in u

rin

e(µ

g/24

hr)

Estrogen secretion throughout the sexual life of the female human being

Guyton & Hall – Textbook of Medical Physiology – fig 81.10

Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig 54-1

6 mo 10-14 yr 50 yr1st2nd

3rdBirth

Trimesters

100

70

10

Plasma gonadotropins (um/M)

Hypothalamic regulation of pituitary gonadotrophin production and release

Ovarian feedback modulation of pituitary gonadotropin production and release

Pulsed release of GnRH by hypothalamus (1 pulse/ 1-2 hr) permits anterior pitutary production and release of FSH and LH (normal)

Presence of pulsed GnRH and low estrogen and progesterone levels result in increased levels of pulsed LH and FSH (negative feedback)

Continuos, excessive, absent or more frequent GnRH release inhibits FSH and LH production and release (downloading)

Presence of pulsed GnRH, rapidly increasing levels of estrogen, and small amounts of progesterone result in hight pulsed LH and moderately increased pulsed FSH levels (positive feedback)

Decreased pulsed release of GnRH decreases LH secretion but increases FSH secretion (slow-pulsing model)

Presence of pulsed GnRH and high levels of estrogen and progesterone result in decreased LH and FSH levels (negative feedback)

Neuroendocrine Regulation of Menstrual Cycle

Hours

Hours

Hours

GnRH

GnRH

GnRH

Estrogen

Estrogen

Estrogen

GnRH

GnRH

GnRH

FSH

LH

FSH

LH

FSH

LH

FSH

LH

FSH

LH

FSH

LH

Hypothalamus GnRH

(pulses /hr)

PituitaryLH-FSH

Ovary Estrogen

Progesterone

Correlation of serum gonadotrophic and ovarian hormone levels and feedback mechanisms

Follicular phaseFSH-LH

(pulses/hr)

2 4 6 8 10 12 14 16 18 20 22 24 26 28Days

500

400

300

200

100

50

40

30

20

10

Menses

Serum levels

LHmlUml

pgml

ngml

Progesterone

10987654321

EstrogenFSH

Luteinizing hormone

Folicular steroid hormones (progesterone)

Proteolytic enzymes (collagenase)

Follicular hyperemia and

prostaglandin secretion

Weakened follicle wallPlasma transudation

into follicle

Degeneration of stigma Follicle swelling

Follicle rupture

Evagination of ovum

Postulated mechanism of ovulation

Guyton & Hall – Textbook of Medical Physiology – fig 81.5

HO

OH

Estradiol

Foyes Principles of Medicinal Chemistry – pag 685

RO

X

OHCCH

RO

OR1

Ethinyl estradiol: R = X = H

Mestranol: R = CH3; X = X

2-Hydroxyethinylestradiol: R = H; X = OH

Estradiol 17β-valerate: R = H: R1 = CH3(CH2)3CO

Estradiol 17β-cyclopentylpropionate

R = HR1 = CH2CH2CO

17α-Ethinyl estrogens, and Estradiol Esters

Foyes Principles of Medicinal Chemistry – fig. 29.6

O

O

Progesterone

Foyes Principles of Medicinal Chemistry – pag 685

O

OHC CH C CCH3

OH

O

OO

O O

H

Ethisterone Dimethisterone

19-Nor-14β, 17α-preg-4-ene-3,20-dione

19-Norprogesterone

Progestins and 19-norandrostane

Foyes Principles of Medicinal Chemistry – fig. 29.16

H3C-C-O

O

O

OC-CH3

C≡CH

O

O O O

O

O

OH

OH

OH OH OH

OH

C≡CH

C≡CH C≡CH C≡CH

C≡CHC≡CHC≡CH

OC-CH3

HON

3-Ketodesogestrel (etonogestrel) Ethynodiol diacetate

Desogestrel Norgestimate Norgestrel

NorethindroneNorethynodrelNorethisterone

Foyes Principles of Medicinal Chemistry – fig. 29.17

19-Norandrostanes used clinically in oral

contraceptives

Estrógenos

• Síntese de DNA e RNA hepático,

• Enzimas hepáticas

• Enzimas séricas formadas no fígado

• Proteínas plasmáticas

Mechanism of Action of Estrogen/Progestin Contraceptives

• Inhibition of ovulation by suppression of follicle-stimulating hormone (FSH) and luteinizing hormone (LH)

•Alteration of cervical mucus to inhibit sperm transport

• Interference with ovum transport

• Inhibition of implantation by suppression of normal endometrial development

Essential of Reproductive Medicine – Tab. 26.1

Estrogen and progesterone

GnRH

Hypothalamus

Anterior pituitary

Combination oral contraceptives (estrogen and

progestin)

FSH LH

Granulosa cellsOvary

Theca cells

Unfavorable endometrial environment

Altered transportation of sperm, egg, fertilized

ovum

Changes cervix environment

Uterus

Normal cervix

Cholesterol

Pregnenolone

Progesterone

Androstenedione

EstroneEstriol Estradiol

O

O

O

HO

O

O

O

OH

OHOHOH

HO HO HO

O

Testosterone

Co

mb

inat

ion

Ora

l Co

ntr

acep

tive

s

Pílula de Primeira Geração

• Etinilestradiol - doses altas (50mcg ou maior)

• Progestágeno - Levonorgestrel, noretisterona ou etinodiol diacetato.

Pílula de segunda geração

•Etinilestradiol (dose até 30 mcg)

•Progestágeno - levonorgestrel ou noretisterona

Pílula de Terceira Geração

• Etinilestradiol (20-30 mcg)

• Progestágeno - desogestrel, gestodeno ou norgestimato

ETINILESTRADIOL + GESTODENO  

etinilestradiol 15 mcg + gestodeno 60 mcg etinilestradiol 20 mcg + gestodeno 75 mcg etinilestradiol 30 mcg + gestodeno75 mcg

MINESSEMIRELLE

DIMINUTFEMIANEGINESSEHARMONETMICROPIL R21TÂMISA 20

CICLO 21GESTINOL 28GYNERAMINULETTÂMISA 30

  ETINILESTRADIOL + DESOGESTREL  

etinilestradiol 20 mcg + desogestrel 150 mcg etinilestradiol 30 mcg + desogestrel 150 mcg)  

FEMINAMERCILONMINIANPRIMERA

MICRODIOL  

  ETINILESTRADIOL+DROSPERINONA  

etinilestradiol 20 mcg + drosperinona 3 mg etinilestradiol 30 mcg + drosperinona 3 mg  

Yaz YASMIN  

  ETINILESTRADIOL+CLORMADINONA  

  etinilestradiol 30 mcg + clormadinona 2mg  

  BELARA  

  ETINILESTRADIOL E OUTROS  

etinilestradiol 30 mcg + levonorgestrel 150 mcg etinilestradiol 20 mcg + levonorgestrel 150 mcgComp. azul: Desogestrel 0,025 mg + Etinilestradiol 0,04

mg; Comp. branco: Desogestrel 0,125 mg + Etinilestradiol 0,03 mg

CICLONGESTRELANNOCICLINMICROVLARNORDETTE

LEVEL GRACIAL

etinilestradiol 50 mcg + levonorgestrel 250 mcg    

EVANORNEOVLAR

Progestin-Only Contraceptives

Mechanism – Altered GnRH release leads to ↓ ovulation

Drug Summary Table – Pharmacology of Reproduction

Norgestrel Norethindrone

Contraception Breakthrough Sporting Norgestrel also available as subdermal implant

Less effective than estrogen/progestin combination

Drug Clinical Uses Side Effects/Toxicities Notes

Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454

Contraceptive use in the United States, 1995.

Essential of Reproductive Medicine – Fig. 26.2

26%24%

19%

7% 6%

3%1% 1% 1%

30

25

20

15

10

5

0

Percentage of Women Ages 15-50

Pill Sterilization Condom Withdrawa/ Rhythm

Hysterectomy/ Menopause

Injectable Spermicide IUD Implants

Method

Noncontraceptive Health Benefits of Oral Contraceptives

Percent Reduction/ Protection

(%)Minium Use

RequiredDuration of

EffectOCP

Formulation CommentsDefinitive evidence

Ovarian cancer 40 3-6 months At least 15 >20 µg EE Also protective against years hereditary ovarian cancer

Endometrial cancer 50 12-months 15 years All monophasic No data on multiphasic or progestin-only forms

Benign breast disease 30 12-24 months 1 year >20 µg EE Effect consistent across all age groups

Pelvic inflamatory 50 12 months Current use >20 µg EE ? Effect on outpatient disease cases of PID

Ectopic pregnancy 90 Current use Current use >20 µg EE No increased risk for ectopic pregnancy in women who become

pregnant with OCP use

Essential of Reproductive Medicine – Tab. 26.2

Noncontraceptive Health Benefits of Oral Contraceptives

Percent Reduction/ Protection

(%)Minium Use

RequiredDuration of

EffectOCP

Formulation CommentsConflicting evidence, favor beneficial effect

Bone mineral density 60 Unknown Unknown >35 µg EE Decreased incidence of hip fractures with higher doses

Colorectal cancer 40 96 months Unknown >50 µg EE Increasing protection with increased duration

Uterine leiomyomas 30, 50 10 years; Unknown Unclear If used in setting of fibroids no 7 years clinically significant uterine growth

Toxic shock syndrome 50 Current use Current use Unclear May be influenced by change in tampon composition/absorbency

Essential of Reproductive Medicine – Tab. 26.2

Noncontraceptive Health Benefits of Oral Contraceptives

Percent Reduction/ Protection

(%)Minium Use

RequiredDuration of

EffectOCP

Formulation CommentsConflicting evidence, favor no effect

Functional ovarian cysts 80, 48, 8 Current use Current use Monophasic No statistically significant effect >35 µg EE;

Monophasic <35 mcg EE

triphasic all types

Rheumatoid arthritis 40 Current use Current use Unclear May alter severity and clinical course rather development

Essential of Reproductive Medicine – Tab. 26.2

Benefícios dos AOC

• Menor risco de câncer endometrial e ovariano.

• Menor risco de prenhez ectópica

• Menstruação mais regular (menor fluxo, menor dismenorréia, menor anemia)

• Menor incidência de salpingite

• Aumento da densidade óssea

AOC e câncer

• Redução de 50% do risco de câncer de endométrico

• Redução de 40% do risco de câncer de ovário

• Sem efeito no câncer de cérvix uterina ou no câncer de mama.

250

200

150

100

50

020-24 25-29 30-34 35-39 40-44

0 0 0

Age group (years)

Dea

ths

/ 100

,000

wom

en nonuser, nonsmokeruser, nonsmokernonuser, heavy smokeruser, heavy smoker

Number of deaths from cardiovascular diseases per 100,000 women by smoking status or nonuse of oral contraceptives.

Essential of Reproductive Medicine – Fig. 26.4

Relative Risk and Actual Incidence of Venous Thromboembolism

Population Relative Risk Incidence

Young women-general population 1 4-5 per 100,000 per year

Pregnant women 12 48-60

High-dose oral contraceptives 6-10 24-50

Low dose oral contraceptives 3-4 12-20

Leiden mutation carrier 6-8 24-40

Leiden carrier and oral contraceptives 10-15 40-75

Leiden mutation – homozygous 80 320-400

A Clinical Guide for Contraception – tab. Pag 53

The carrier frequencies of the Leiden mutation in American population (the percentages are similar in men and women) are as

follows

Caucasian Americans 5.27%

Hispanic Americans 2.21%

Native Americans 1.25%

Black Americans 1.23%

Asian Americans 0.45%

A Clinical Guide for Contraception – tab. Pag 53

In the Transnational case-control study of myocardial infarctions collected from 16 centers in Austria, France, Germany, Switzerland, and United

Kingdom, the results were as follows

ConfidenceCases Controls Odds Ratio Interval

Any OC use 57 156 2.35 1.42-3.89

50 µg estrogen OCs 14 22 4.32 1.59-11.74

Old progestin OCs 28 71 2.96 1.54-5.66

New progestin OCs 7 49 0.82 0.29-2.31

A Clinical Guide for Contraception – tab. Pag 55

Incidence of Myocardial Infarction in Reproductive Age Women

Overall incidence 5 per 100,000 per year

Women less than age 35

Nonsmokers 4

Nonsmokers & OCs 4

Smokers 8

Smokers & OCs 43

Women 35 years old and older

Nonsmokers 10

Nonsmokers & OCs 40

Smokers 88

Smokers & OCs 485

A Clinical Guide for Contraception – tab. Pag 57

Incidence of Stroke in Reproductive Age Women

Incidence of

ischemic stroke 5 per 100,000 per year

1-3 per year in women under age 35

10 per 100,000 per year in women over age 35

Incidence of

hemorrhagic stroke 6 per 100,000 per year

Excess cases 2 per 100,000 per year in low-dose OC users

per year due to 1 per 100,000 per year in low-dose OC users under age 35

OCs, including 8 per 100,000 per year in high-dose users

smokers and

hypertensives

A Clinical Guide for Contraception – tab. Pag 61

Possible Contradications to Use of Combined Oral Contraceptive Pills

Absolute Contraindications

1. Thrombophlebitis or Thromboembolic disorders

2. Past history of deep vein thrombophlebitis or thromboembolic disorders

3. Cerebrovascular or coronary artery disease

4. Known or suspected breast carcinoma

5. Known or suspected estrogen-dependent neoplasia

6. Pregnancy

7. Benign or malignant liver tumor

8. Known impaired liver function

9. Previous cholestasis during pregnancy or with prior pill use

Essential of Reproductive Medicine – Tab. 26.6

Possible Contradications to Used of Combined Oral Contraceptive Pills (cont)

Strong Relative Contraindications

10. Severe headaches, particularly vascular or migraine headaches, that start after initiation of oral contraceptives

11. Hypertension with resting diastolic BP of 140 mmHg or greater on three or more separate visits or an accurate measurement of 110 mmHg diastolic or more on single visit

12. Mononucleosis, acute phase

13. Elective major surgery or major surgery requiring immobilization planned in next 4 week

14. Long-leg cast or major injury to lower leg

15. Over 40 years old, accompanied by a second risk factor for the development of cardiovascular disease (such as diabetes or hypertension)

16. Over 35 years old and currently a heavy smoker (15 or more cigarettes/day)

17. Abnormal genital bleeding

Essential of Reproductive Medicine – Tab. 26.6

Possible Contradications to Used of Combined Oral Contraceptive Pills (cont)

Other Considerations

• Diabetes, prediabetes, or a strong family history of diabetes

• Sickle cell disease or sickle C disease

• Active gallbladder disease

• Congenital hyperbilirubinemia (Gilbert’s disease)

• Undiagnosed abnormal genital bleeding

• Over 50 years old

• Completion of term pregnancy within past 10 to 14 days

• Weight gain of 10 lb or more while on the pill

• Cardiac renal disease (or history thereof)

• Conditions likely to make patient unreliable at following pill instructions (mental retardation, major psychiatric illness, alcoholism, or other chemical abuse, history of repeatedly taking oral contraceptives or other medication incorrectly)

• Lactation

• Family history of death of a parent or sibling due to myocardial infarction before age 50; myocardial infarction in a mother or sister is especially significant and indicates a need for lipid evaluation

• Family history of hyperlipidemia

Essential of Reproductive Medicine – Tab. 26.6

AOC e Fígado

Transporte ativo de componentes biliares é inibido por estrógenos e progestágenos.

Contraindicado formalmente em doença colestática aguda ou crônica

Importante

Não há evidências de aumento de incidência de doença hepática séria causado por uso de ACO

Contraceptivo Oral e Trombose

• Estrógenos, mas não progestágenos, aumentam a produção de fatores de coagulação.

• Tabagismo e uso de estrógenos apresentam efeito aditivo no risco de trombose arterial.

• Contraceptivos de dose baixa de estrógeno (< 50 microg EE) não aumentam o risco de IM ou AVC em mulheres saudáveis, não fumantes, independente da idade.

• IM e AVC podem ocorrer em mulheres que usam contraceptivos de alta dose, ou que apresentam fatores de risco cardiovascular acima da idade de 35 anos.

Anel Vaginal (RING)

Emplastro dérmico (patch)

40 mm

2 mm

Rate-controlling membrane: (.06 mm) 100% EVA

Core: 40% Ethylene vinyl acetate (EVA)

60% Etogestrel (68 mg)

Required Equipment for Implanon Insertion

Implantation technique

Technique for the Tcu-380A

Progesterone Receptor Antagonists

Mechanism – Inhibit progesterone binding to receptor

Drug Summary Table – Pharmacology of Reproduction

Mifepristone Medical abortion Bleeding Must be able to verify age of fetus

Coadministered with misoprostol (causes ulterine contractions, nausea)

Antagonist at glucocorticoid receptor as well as progesterone receptor

Drug Clinical Uses Side Effects/Toxicities Notes

Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454

Progesterone Receptor Antagonists (Cont.)

Mechanism – Inhibit progesterone binding to receptor

Drug Summary Table – Pharmacology of Reproduction

Mifepristone Pregnancy >49 days

Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454

Drug Interactions / Contraindications

Mixed Estrogen / Progestin Oral ContraceptivesMechanism – Suppres follicular development; inhibit midcycle surge of LH and FSH, inhibit ovulation

Drug Summary Table – Pharmacology of Reproduction

Estrogens

Ethinyl Estradiol

Mestranol

Progestins

Norgestrel,

levonorgestrel

Norethindrome

Ethynodiol,

norgestimate

Desogestrel

Prevention of pregnancy

Postcoital contraception

Slightly ↑ risk stroke

↑ Triglyceride levels

↑ Risk DVT

Drug Clinical Uses Side Effects/Toxicities Notes

Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454

Breakthrough bleeding

↑ Blood pressure

Formulation exist as monophasic, biphasic, triphasic dosage forms

Monofasic: Constant estrogen and progestin

Biphasic: Higher progestin in second half of cycle + midcycle ↑ estrogen

Triphasic: higher progestin in second half of cycle + midcycle ↑ estrogen

No Clinical differences in efficacy or side effects among monophasic, biphasic or triphasic

Mixed Estrogen / Progestin Oral Contraceptives (Cont.)Mechanism – Suppres follicular development; inhibit midcycle surge of LH and FSH, inhibit ovulation

Drug Summary Table – Pharmacology of Reproduction

Estrogens

Ethinyl Estradiol

Mestranol

Progestins

Norgestrel,

levonorgestrel

Norethindrome

Ethynodiol,

norgestimate

Desogestrel

Contraindications:

Previous DVT or stroke

History of strogen-dependent tumor

Liver Disease

Pregnancy

Hypertriglyceridemia

Women > 35 y/o who smoke

Drug Interactions:

Rifampin, phenytoin, and phenobarbital

all ↑ metabolism of OCPs

Drug Interactions/Contraindications

Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454

Progestins Used in Breast Cancer

Mechanism – Unknown

Drug Summary Table – Pharmacology of Reproduction

Megestrol acetate Medroxyprogesterone acetate

Advanced breast cancer ↑ Risk DVT

Hot flashes

Drug Clinical Uses Side Effects/Toxicities

Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454

Testosterone

O

OH

Foyes Principles of Medicinal Chemistry – pag 685

O

OH

H

5α-Dihydrotestosterone

Foyes Principles of Medicinal Chemistry – pag 685

HO

O

Estrone

Foyes Principles of Medicinal Chemistry – pag. 686

Estriol

HO

OH

OH

Foyes Principles of Medicinal Chemistry – pag. 686

Foy

es P

rinc

iple

s of

Med

icin

al C

hem

istr

y –

fig.

29.

3

HOCholesterol

O

HO

HO

OH

O O

O

Pregnenolone

17α-Hydroxypregnenolone Progesterone

a

b c,d

HO

O O O

O

O

HO

c,d g

OH

O

OOH

HO

OH

OH

i g

f h

e

Dehydroepiandrosterone Androstenedione Estrone

5α-Dihydrotestosterone Testosterone Estradiol

Biosynthesis of sex steroid hormones

Estrogen metabolism

Foy

es P

r inc

i ple

s of

Med

ici n

al C

hem

i str

y –

fig.

29.

5

HO

O O

O

RO

RO

EquilinEquilin sodium sulfate

EstroneEstrone sodium sulfate

Piperazine estrone sulfate

R = HR = SO3 –Na+

R = HR = SO3 –Na+

R = SO3 + N NHH

H

Conjugated and esterified estrogens

Foyes Principles of Medicinal Chemistry – fig. 29.7

O

O

O

O OOH

OH

HOH

CH

5β-Pregnanediol 6α-Hydroxyprogesterone 20α/β-Hydroxyprogesterone

OH

H

H

Conformation of rings A and B for 5β-preganediol

Progesterone

Conformation of rings A and B for progesterones

Metabolism of progesterone

Foyes Principles of Medicinal Chemistry – fig. 29.14

OH

HO

OH

O HOH

O

OHOH

OH

HO

OH

HH

O

OO

O

Testosterone

Epi-testosterone AndrosteroneEstradiol

6α-Hydroxytestostenore

5α-Dihydrotestosterone etiocholanolone

O

OH

H

H

HO

Conformation of rings A and B for 5α-dihydrotestosterone

Conformation of rings A and B for testosterone Conformation of rings A and B

for etiocholanolone

Metabolism of testosterone

Foy

es P

rinc

iple

s of

Med

icin

al C

hem

istr

y –

fig.

29.

18

CH3CH3

H3C N H3CN

O O

OH OHCH2-CH2CH2OHC ≡ CCH3

Mifepristrone Onapristrone

Foyes Principles of Medicinal Chemistry – pag. 703

The tetracyclic ring system characteristic of steroids

Organic Chemistry – fig. 26.9