Download FSH - Stoa Social

Dúvidas
[email protected]
Arquivo
Medicamentos atuantes no sistema
reprodutivo feminino - Anticoncepcionais
Site
www.gdenucci.com
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
Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig 54-1
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
400
200
8
6
4
2
0
800
0
LH
600
400
Progesterone (ng/ml)
Menstruation
600
Progesterone
Ovulation
FSH and LH (ng/ml)
Estradiol (pg/ml)
800
Ovulation
Approximate plasma concentrations of the gonadotropins and ovarian
hormones during the normal female sexual cycle
FSH
200
0
0
2
4
6
8
10 12 14 16 18 20 22 24 26 28
Days of female sexual cycle
Guyton & Hall – Textbook of Medical Physiology – fig 81.3
Menopause
400
Puberty
Estrogens excreted in urine
(µg/24 hr)
Estrogen secretion throughout the sexual life of the female human being
300
200
100
0
0-----12
13------40
Age (yr)
50
60
Guyton & Hall – Textbook of Medical Physiology – fig 81.10
Plasma
100
gonadotropins
(um/M)
70
10
6 mo
10-14 yr
50 yr
Trimesters
Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig 54-1
Neuroendocrine Regulation of Menstrual Cycle
Hypothalamic regulation of pituitary
gonadotrophin production and release
Hours
FSH
Ovarian feedback modulation of pituitary
gonadotropin production and release
GnRH
FSH
Estrogen
GnRH
LH
Pulsed release of GnRH by hypothalamus (1 pulse/ 1-2 hr)
permits anterior pitutary production and release of FSH
and LH (normal)
LH
Presence of pulsed GnRH and low estrogen and progesterone
levels result in increased levels of pulsed LH and FSH
(negative feedback)
Hours
FSH
GnRH
LH
Continuos, excessive, absent or more frequent GnRH
release inhibits FSH and LH production and release
(downloading)
Hours
GnRH
Estrogen
FSH
FSH
LH
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)
FSH
GnRH
Estrogen
GnRH
LH
Decreased pulsed release of GnRH decreases LH
secretion but increases FSH secretion (slow-pulsing
model)
LH
Presence of pulsed GnRH and high levels of estrogen and
progesterone result in decreased LH and FSH levels (negative
feedback)
Correlation of serum gonadotrophic and ovarian hormone levels and
feedback mechanisms
FSH-LH
(pulses/hr)
Follicular phase
Hypothalamus
GnRH
(pulses /hr)
Pituitary
LH-FSH
Ovary
Estrogen
Progesterone
FSH
50
Estrogen
500
10
9
8
7
6
5
4
3
2
1
400
40
Serum levels
30
300
20
200
10
100
Progesterone
ng
pg
ml
ml
Menses
2
4
6
8
10
12
14
16 18
Days
20
22
24
26
28
LH
mlU
ml
Postulated mechanism of ovulation
Luteinizing hormone
Folicular steroid hormones
(progesterone)
Proteolytic enzymes
(collagenase)
Follicular hyperemia
and
prostaglandin secretion
Weakened follicle wall
Plasma transudation
into follicle
Degeneration
of stigma
Follicle swelling
Follicle rupture
Evagination of ovum
Guyton & Hall – Textbook of Medical Physiology – fig 81.5
OH
HO
Estradiol
Foyes Principles of Medicinal Chemistry – pag 685
17α-Ethinyl estrogens, and Estradiol Esters
OR1
OH
CCH
X
RO
RO
Ethinyl estradiol: R = X = H
Estradiol 17β-valerate: R = H: R1 = CH3(CH2)3CO
Mestranol: R = CH3; X = X
Estradiol 17β-cyclopentylpropionate
2-Hydroxyethinylestradiol: R = H; X = OH
R=H
R1 =
CH2CH2CO
Foyes Principles of Medicinal Chemistry – fig. 29.6
O
O
Progesterone
Foyes Principles of Medicinal Chemistry – pag 685
Progestins and 19-norandrostane
OH
OH
C  CH
O
C  CCH3
O
Ethisterone
Dimethisterone
O
O
H
O
19-Nor-14β, 17α-preg4-ene-3,20-dione
O
19-Norprogesterone
Foyes Principles of Medicinal Chemistry – fig. 29.16
19-Norandrostanes
used clinically in oral
contraceptives
OH
C≡CH
O
OH
C≡CH
O
O
Norethisterone
OH
C≡CH
Norethindrone
Norethynodrel
O
OH
C≡CH
HO
Desogestrel
N
Norgestimate
O
C-CH3
OH
C≡CH
C≡CH
O
Norgestrel
O
OH
O
C≡CH
O
3-Ketodesogestrel (etonogestrel)
C-CH3
C≡CH
O
H3C-C-O
Ethynodiol diacetate
Foyes Principles of Medicinal Chemistry – fig. 29.17
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
Combination Oral Contraceptives
Hypothalamus
Combination oral
contraceptives
(estrogen and
progestin)
GnRH
Estrogen and
progesterone
Anterior
pituitary
FSH
Unfavorable
endometrial
environment
LH
Altered transportation of
sperm, egg, fertilized
ovum
Granulosa cells
Ovary
Uterus
Cholesterol
O
Changes cervix
environment
Theca cells
HO
Pregnenolone
O
O
Progesterone
O
OH
O
O
Androstenedione
OH
Testosterone
O
OH
OH
HO
HO
Estriol
HO
Estrone
Estradiol
Normal cervix
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
MINESSE
MIRELLE
etinilestradiol 20 mcg + gestodeno 75 mcg
DIMINUT
FEMIANE
GINESSE
HARMONET
MICROPIL R21
TÂMISA 20
etinilestradiol 30 mcg + gestodeno75 mcg
CICLO 21
GESTINOL 28
GYNERA
MINULET
TÂMISA 30
ETINILESTRADIOL + DESOGESTREL
etinilestradiol 20 mcg + desogestrel 150 mcg
FEMINA
MERCILON
MINIAN
PRIMERA
etinilestradiol 30 mcg + desogestrel 150 mcg)
MICRODIOL
ETINILESTRADIOL+DROSPERINONA
etinilestradiol 20 mcg + drosperinona 3 mg
Yaz
etinilestradiol 30 mcg + drosperinona 3 mg
YASMIN
ETINILESTRADIOL+CLORMADINONA
etinilestradiol 30 mcg + clormadinona 2mg
BELARA
ETINILESTRADIOL E OUTROS
etinilestradiol 30 mcg + levonorgestrel 150 mcg
CICLON
GESTRELAN
NOCICLIN
MICROVLAR
NORDETTE
etinilestradiol 50 mcg + levonorgestrel 250 mcg
EVANOR
NEOVLAR
etinilestradiol 20 mcg + levonorgestrel 150 mcg
LEVEL
Comp. azul: Desogestrel 0,025 mg + Etinilestradiol 0,04
mg; Comp. branco: Desogestrel 0,125 mg +
Etinilestradiol 0,03 mg
GRACIAL
Drug Summary Table – Pharmacology of Reproduction
Progestin-Only Contraceptives
Mechanism – Altered GnRH release leads to ↓ ovulation
Drug
Clinical Uses
Norgestrel
Norethindrone
Contraception
Side Effects/Toxicities
Notes
Breakthrough Sporting Norgestrel also available
as subdermal implant
Less effective than
estrogen/progestin
combination
Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454
Contraceptive use in the United States, 1995.
Percentage of Women Ages 15-50
30
26%
25
24%
20
19%
15
10
7%
6%
5
3%
0
Pill
Sterilization
Condom
Withdrawa/ Hysterectomy/ Injectable
Rhythm
Menopause
1%
1%
Spermicide
IUD
1%
Implants
Method
Essential of Reproductive Medicine – Fig. 26.2
Noncontraceptive Health Benefits of Oral Contraceptives
Definitive evidence
Percent
Reduction/
Protection
(%)
Minium Use Duration of
Required
Effect
Ovarian cancer
40
3-6 months
Endometrial cancer
50
Benign breast disease
OCP
Formulation
Comments
At least 15
years
>20 µg EE
12-months
15 years
All monophasic No data on multiphasic or
progestin-only forms
30
12-24 months
1 year
>20 µg EE
Pelvic inflamatory
disease
50
12 months
Current use >20 µg EE
Ectopic pregnancy
90
Current use
Current use >20 µg EE
Also protective against
hereditary ovarian cancer
Effect consistent across all age groups
? Effect on outpatient
cases of PID
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
Conflicting evidence,
favor beneficial effect
Percent
Reduction/
Protection
(%)
Minium Use Duration of
Required
Effect
OCP
Formulation
Comments
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;
7 years
Unknown
Unclear
If used in setting of fibroids no
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
Conflicting evidence,
favor no effect
Percent
Reduction/
Protection
(%)
Minium Use Duration of
Required
Effect
Functional ovarian cysts 80, 48, 8 Current use
Rheumatoid arthritis
40
Current use
OCP
Formulation
Comments
Current use
Monophasic
No statistically significant effect
>35 µg EE;
Monophasic
<35 mcg EE
triphasic all types
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.
Number of deaths from cardiovascular diseases per 100,000
women by smoking status or nonuse of oral contraceptives.
Deaths / 100,000 women
250
200
nonuser, nonsmoker
user, nonsmoker
nonuser, heavy smoker
user, heavy smoker
150
100
50
0
00
0
20-24
25-29
30-34
35-39
40-44
Age group (years)
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
Confidence
Interval
Cases
Controls
Odds Ratio
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
Core:
40% Ethylene vinyl acetate (EVA)
60% Etogestrel (68 mg)
Rate-controlling membrane: (.06 mm) 100% EVA
Required Equipment for Implanon Insertion
Implantation technique
Technique for the
Tcu-380A
Drug Summary Table – Pharmacology of Reproduction
Progesterone Receptor Antagonists
Mechanism – Inhibit progesterone binding to receptor
Drug
Clinical Uses
Mifepristone
Medical abortion
Side Effects/Toxicities
Bleeding
Notes
Must be able to verify age
of fetus
Coadministered with
misoprostol (causes
ulterine contractions,
nausea)
Antagonist at
glucocorticoid receptor as
well as progesterone
receptor
Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454
Drug Summary Table – Pharmacology of Reproduction
Progesterone Receptor Antagonists (Cont.)
Mechanism – Inhibit progesterone binding to receptor
Drug
Interactions / Contraindications
Mifepristone
Pregnancy >49 days
Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454
Drug Summary Table – Pharmacology of Reproduction
Mixed Estrogen / Progestin Oral Contraceptives
Mechanism – Suppres follicular development; inhibit midcycle surge of LH and FSH, inhibit ovulation
Drug
Clinical Uses
Estrogens
Prevention of pregnancy
Breakthrough bleeding
Ethinyl Estradiol
Postcoital contraception
↑ Blood pressure
Mestranol
Slightly ↑ risk stroke
Progestins
↑ Triglyceride levels
Norgestrel,
↑ Risk DVT
levonorgestrel
Side Effects/Toxicities
Notes
Formulation exist as
monophasic, biphasic, triphasic
dosage forms
Monofasic: Constant estrogen
and progestin
Biphasic: Higher progestin in
second half of cycle + midcycle
↑ estrogen
Norethindrome
Ethynodiol,
norgestimate
Desogestrel
Triphasic: higher progestin in
second half of cycle + midcycle
↑ estrogen
No Clinical differences in
efficacy or side effects among
monophasic, biphasic or
triphasic
Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454
Drug Summary Table – Pharmacology of Reproduction
Mixed Estrogen / Progestin Oral Contraceptives (Cont.)
Mechanism – Suppres follicular development; inhibit midcycle surge of LH and FSH, inhibit ovulation
Drug
Interactions/Contraindications
Estrogens
Contraindications:
Ethinyl Estradiol
Previous DVT or stroke
Mestranol
History of strogen-dependent tumor
Progestins
Liver Disease
Norgestrel,
Pregnancy
levonorgestrel
Hypertriglyceridemia
Norethindrome
Women > 35 y/o who smoke
Ethynodiol,
Drug Interactions:
norgestimate
Desogestrel
Rifampin, phenytoin, and phenobarbital
all ↑ metabolism of OCPs
Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454
Drug Summary Table – Pharmacology of Reproduction
Progestins Used in Breast Cancer
Mechanism – Unknown
Drug
Clinical Uses
Side Effects/Toxicities
Megestrol acetate
Medroxyprogesterone acetate
Advanced breast cancer
↑ Risk DVT
Hot flashes
Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454
OH
O
Testosterone
Foyes Principles of Medicinal Chemistry – pag 685
OH
O
H
5α-Dihydrotestosterone
Foyes Principles of Medicinal Chemistry – pag 685
O
HO
Estrone
Foyes Principles of Medicinal Chemistry – pag. 686
OH
OH
HO
Estriol
Foyes Principles of Medicinal Chemistry – pag. 686
Biosynthesis of sex
steroid hormones
HO
Cholesterol
a
b
O
HO
Pregnenolone
O
OH
c,d
O
HO
e
Progesterone
O
O
g
c,d
HO
O
HO
Dehydroepiandrosterone
Androstenedione
f
OH
5α-Dihydrotestosterone
Estrone
h
OH
OH
g
i
H
O
HO
O
Testosterone
Estradiol
Foyes Principles of Medicinal Chemistry – fig. 29.3
17α-Hydroxypregnenolone
O
O
Estrogen metabolism
Conjugated and esterified estrogens
O
O
RO
HO
Equilin
Equilin sodium sulfate
O
RO
Estrone
Estrone sodium sulfate
Piperazine estrone sulfate
R=H
R = SO3 –Na+
R=H
R = SO3 –Na+
H
R = SO3 + N
H
NH
Foyes Principles of Medicinal Chemistry – fig. 29.7
Metabolism of progesterone
O
O
Progesterone
OH
HO
O
O
H
O
OH
5β-Pregnanediol
CH
6α-Hydroxyprogesterone
20α/β-Hydroxyprogesterone
H
H
OH Conformation of rings A and B
for 5β-preganediol
Conformation of rings A and B
for progesterones
Foyes Principles of Medicinal Chemistry – fig. 29.14
Metabolism of testosterone
O
OH
OH
HO
O
HO
Estradiol
Epi-testosterone
H
Androsterone
OH
OH
O
O
OH
Testosterone
6α-Hydroxytestostenore
HO
O
H
H
etiocholanolone
5α-Dihydrotestosterone
H
O
H
Conformation of rings A and B
for 5α-dihydrotestosterone
O
Conformation of rings A and B
for testosterone
H
OH Conformation of rings A and B
for etiocholanolone
Foyes Principles of Medicinal Chemistry – fig. 29.18
O
OH
CH3
H3C N
OH
C ≡ CCH3
CH3
H3C N
OH
CH2-CH2CH2OH
O
O
Mifepristrone
Onapristrone
Foyes Principles of Medicinal Chemistry – pag. 703
The tetracyclic ring system characteristic of steroids
Organic Chemistry – fig. 26.9