GnRH

Report
Dr. Kaukab Azim. MBBS, PhD
1
• Hypogonadism in males and females
• Precocious puberty, leiomyoma, endometriosis,
dysmenorhea
• Hormonal contraceptives
• Menopausal replacement therapy
• Infertility
• SERMs
• Medical abortion
• Gonadal hormones agonist and antagonists
• Hormonal drugs for some cancers
Gonadal Hormones and Inhibitors
Hypothalamic
and
ant. pituitary
hormones
Estrogens
&
Inhibitors
Progestins
&
Inhibitors
Natural and
synthetic
Androgens
&
Inhibitors
GnRH analogs
Natural &
Synthetic
Natural and
synthetic
GnRH
antagonists
SERMs
Anabolic steroids
Gonadotropins:
FSH
LH
Partial agonists & Antagonist
antagonists
Antiandrogens
-Gn release inhibitors
-Receptors inhibitors
-5-a reductase inhibitor
-Synthesis inhibitor
Aromatase
inhibitors
3
Hypothalamus-Pituitary-Gonadal Axis
Key concepts of Pharmacology
of Gonadal Hormones:
(Ovulation inducer)
•
Effects of GnRH release frequency on
gonadotropin release.
•
Interaction between estrogen and the
pituitary gland.
•
Tissue selectivity of estrogen agonists
and antagonists.
•
Various strategies to antagonize the
effect of endogenous sex hormones.
4
Gonadotropin releasing hormone
(GnRH)
released in “pulsalite manner” from the
hypothalamus and acts on Pituitary to
stimulate the secretion of
gonadotropinsFSH & LH
5
GnRH analogs
Short-acting analogs
• Gonadorelin (t1/2 = 4 min.)
It can be used in “Pulsatile”
manner to stimulate pituitary
to secrete FSH and LH.
Uses:
• Diagnostic purpose
• In infertility: Hypothalamic
amenorrhea
Long-acting analogs
• Goserelin
• Nafarelin- nasal spray
• Leuprolide
After initial stimulation, they
will cause suppression of
gonadotropin (FSH, LH)
secretion.
(down-regulation)
6
GnRH analogs
Long-acting GnRH analogs
• Goserelin
• Nafarelin
• Leuprolide
After initial stimulation, they
will cause suppression of
gonadotropin (FSH, LH)
secretion.
•
•
•
•
•
Therapeutic Uses:
For Medical castration:
In precocious puberty
Breast Ca
Prostate Ca
Leiomyoma
Endometriosis
7
GnRH analogs: Adverse effects
Adverse effects of long-acting analogs:
• Gonadal steroidal inhibition in females can
cause:
– Hot flashes
– Vaginal atrophy
– Decreased bone density
8
GnRH antagonist
– Ganirelix
– Cetrorelix
These are pure GnRH antagonists and do not
cause initial increase in gonadotropin
secretion.
9
Gonadotropins: FSH & LH
Gonadotropin preparations:
– Menotropins (LH + FSH)
– Recombinant FSH and LH
– hCG (Human chorionic gonadotropin)
10
Estrogens
Physiological Role:
• Secondary sexual characteristics
• Menstrual cycle
– During follicular phase it cause endometrium to
grow
• For normal mineralization and osteoid formation
– Deficiency of estrogens cause osteoporosis
11
Estrogens
Natural estrogens
• Estradiol
• Estriol
• Estrone
Synthetic estrogens
• Ethinyl estradiol
• Mestranol
12
Estrogens
• Oral:
– Estradiol: micronized form
– Conjugated estrogens: conjugated equine estrogens
– Ethinyl estradiol & Mestranol (synthetic estrogens)
• IM: aqueous or oil based esters of estradiol and estrione
• Transdermal preparations: estradiol
13
Uses of Estrogens
• Hormone Replacement therapy:
– Primary hypogonadism
– Premature ovarian failure; surgical removal of ovaries
– Menopause
• Oral contraception
• Osteoporosis
• Atrophic vaginitis
14
Estrogens: Adverse effects
•
•
•
•
•
•
•
Nausea, vomiting
Thromboembolic problems
Myocardial infarction
Breast Ca
Endometrial Ca
Postmenopausal uterine bleeding
Diethylstilbestrol: Clear cell Ca (cervical & vagina)
15
Progestins
• Physiological role:
– helps maintaining pregnancy
• They are often combined with estrogen in various
formulations to counteract the harmful effects of
estrogens
– Estrogen can cause endometrial carcinoma
16
Progestins
Natural progestins:
– Progesterone, 17-alpha hydroxyprogesterone
Synthetic progestins:
–
–
–
–
–
–
Hydroxyprogesterone (IM, every 1-2 weeks)
Medroxyprogesterone (Oral-daily, IM every 1-3 months)
Norethindrone: belongs to 19-nortestoserone analogs
Norgestrel, Levonorgestrel
Norgestimate (less androgenic)
Desogestrel (less androgenic)
17
Progestins: Uses
• As contraceptive and menopausal hormone therapy
– Combined with estrogen (in COCPs & menopausal hormonal
therapy)
– Progestin only contraceptive preparations
– As postcoital contraception
• Dysmenorrhea
• Dysfunctional uterine bleeding
• Endometriosis
18
Progestines: Adverse effects
– Edema
– Depression
ADRs of progestins having Androgen-like activity:
– Increase the ratio of LDL to HDL cholesterol
– Thrombophlebitis
– Pulmonary embolism
– Acne
– Hirsutism
– Weight gain
19
Hormonal Contraceptives
• Combined Oral Contraceptive Pills (COCPs)
– contain both estrogen and progesterone
– Monophasic, Biphasic, Triphasic forms
• Progestin only preparations
– Progestin-only pills (“mini-pill”)
– Progestin implants/depot (Levonorgestrel, medroxyprogesterone)
– Progestin containing Intrauterine device
• Postcoital contraception (emergency contraception)
20
COCPs: Mechanism of action
Feedback inhibition
↓ LH surge
2. Progestins thicken the
cervical mucous and
prevent the entry of
sperm.
No Ovulation
1. Estrogen and progesterone
causes feedback inhibition
of FSH and LH secretion
from the pituitary gland to
inhibit ovulation.
(main mechanism)
3. Effects on uterine tubes and
endometrium decrease the
likelihood of fertilization
and implantation
21
COCPs: Adverse effects
•
•
•
•
•
•
Nausea, vomiting, mastalgia
Headache
Breakthrough bleeding
Wt. gain
Acne and Hirsutism (19-nortestosterone derivatives)
Chloasma (skin pigmentation)
22
COCPs: Serious complications
• Leg vein and pulmonary thrombosis
• Coronary and cerebral thrombosis
• Rise in BP
23
COCPs: Contraindications
COCPs are absolutely contraindicated in
• Thromboembolic, coronary, cerebrovascular disease.
Greater risk for :
– Women > 35 years of age
– Heavy smokers
– Obese
• Active liver disease
• Suspected or overt malignancy of genitals/breast
• Undiagnosed vaginal bleeding
24
COCPs: Relative contraindications
•
•
•
•
•
•
Hypertension
Migraine
Diabetes mellitus
Uterine leiomyoma
Mental illness
Gall bladder disease
25
COCPs: Drug Interactions
• Enzyme inducers (Phenytoin, barbiturates, carbamazapine,
Rifampin) cause contraceptive failure
• Antibiotics (Tetracyclines, ampicillin, etc.) cause contraceptive
failure by suppressing intestinal microflora:
– Decreased deconjugation of estrogens excreted in bile
– Decreased enterohepatic circulation of estrogens
– Blood levels of estrogens fall
contraceptive failure
26
Progestin-only preparations
• Progestin-only pill (“Mini-pill”)
– norethindrone or levonorgestrel
• Progestin implants/depot
– Levonorgestrel: subcutaneous implant, 5 years
– Medroxyprogesterone acetate (DMPA): IM, every 3
months.
• Progestin containing Intrauterine devices
– Progestasert contains progesterone & mirena contains levonorgestrel
27
Progestin-only preparations
Progestin-only preparations are suitable for women
when estrogens are contraindicated :
•
•
•
•
•
Smokers
Age > 35 years
h/o cardiovascular disease
Migraine
Liver impairment
28
Progestin-only preparations
Disadvantages of progestins:
• Frequent spotting
• Irregular and unpredictable menstrual cycles
• Failure rate is higher as compared to combined
COCPs
• Unfavorable effect on lipid profile
29
Emergency contraception
•
Postcoital or “morning after” contraception
1. Combined oral contraceptive pills: 2 pills within 72
hours of unprotected sexual intercourse and 2 exactly 12
hours later.
2. Progestin-only pills (Levonorgestrel): one tablet within
72 hours of unprotected sexual intercourse followed by
second dose exactly 12 hrs later.
3. Ulipristal: a selective progesterone receptor modulator;
taken within 120 hrs of unprotected sexual intercourse
30
Menopausal hormone therapy
(HRT)
• Estrogen deficiency symptoms:
– Hot flashes, chills, night sweats, mood swings, insomnia,
headache, palpitation
– Vaginal and urethral atrophy
– Osteoporosis (others drugs are preferred)
• Lowest effective dose of estrogen for the
shortest duration to relieve estrogen
deficiency symptoms in postmenopausal
period.
31
Selective estrogen receptor modulators
(SERMs)
Tamoxifen, Raloxifene
These are drugs that interact with estrogen receptors but
have different effects on different tissues. They can show
agonism or antagonism depending upon the tissue type.
32
Tamoxifen
• Antiestrogenic effect: on Breast
– Effective in the treatment of breast Ca in patients with tumor
cells that are estrogen receptor- positive.
– can be given after surgery to eradicate micrometastases
• Estrogenic effect: on Endometrium
– Can cause endometrial Ca
– Not prescribed to treat breast Ca for longer than 3-5 years in
non-hysterectomized women
33
Tamoxifen: Adverse effects
•
•
•
•
•
Nausea/Vomiting
Hot flashes
Vaginal bleeding
Risk of Endometrial Ca
Thromboembolic disorders
34
Raloxifene
• Antiestrogenic effect: Breast, Endometrium
• Estrogenic effect: Bones, lipid metabolism
– Unlike Tamoxifen, it does not increase the risk of
endometrial Ca.
– Approved to be used for the prevention of osteoporosis in
postmenopausal women
35
Estrogen antagonists
• Clomiphene (Ovulation inducer):
blocks estrogen receptors in the hypothalamus and anterior
pituitary
reduces negative feedback
↑ FSH and LH secretion
ovarian follicle development and ovulation
• Fulvestrant
36
Progesterone antagonist
• Mifepristone (RU 486)
– Progesterone receptor antagonist
– Glucocorticoid receptor antagonist
Therapeutic uses:
– Medical termination of pregnancy
(Mifepristone followed 48 hrs later by Misoprostol)
37
Aromatase inhibitors
• Anastrozole, Letrozole : non-steroidal agents;
competitive inhibitors
• Exemestane : steroidal agent; irreversible inhibitor
Estriol
Estrone
Estradiol
38
Aromatase inhibitors
• Aromatase inhibitors block the synthesis of estrogens
from androgen precursors by inhibiting aromatase
enzyme.
• This approach can be used to inhibit the growth of
estrogen-dependent tumors e.g., breast cancer.
• Used in postmenopausal women with advanced
breast cancer
– Unlike tamoxifen, they do not increase the risk of
endometrial carcinoma or venous
thromboembolism.
• Endometriosis
39
Androgens
Testosterone esters:
• Testosterone propionate
• Testosterone enanthate
• Testosterone cypionate
17-alpha alkylated androgens:
• Methyltestosterone
• Fluoxymesterone
• Oxandrolone (anabolic steroid)
• Danazol (Danocrine)
40
Androgens: Therapeutic Uses
• Hypogonadism: as hormonal replacement therapy.
• For Anabolic effects:
– Osteoporosis
– severe burns
– to increase lean body mass, muscle strength
• Endometriosis
• Hereditary angioedema
41
Danazol
synthetic derivative of 17-ethinyltestosterone
• It has weak androgenic, progestational and
glucocorticoid activity
• Inhibits CYP450 enzymes involved in gonadal
hormone synthesis
Uses:
– Endometriosis
– Fibrocystic breast disease
– Hereditary angioedema (It occurs due to deficiency of C1esterase inhibitor)
42
Danazol: Adverse effects
•
•
•
•
•
•
Acne
Hirsutism
Menstrual irregularities
Hepatotoxicity
Thromboembolism
Teratogenic
43
Anabolic steroids
• Greater anabolic:androgenic activity
• Oxandrolone (anabolic: androgenic=3:1-13-1)
Adverse drug reactions:
• Infertility: due to suppressed FSH and LH
– Decreased testicular size and function
• Feminization in men, gynecomastia
• Masculinization in women: Hirsutism, deepening of
voice, menstrual irregularities
• Hepatic dysfunction, Cholestatic jaundice
• Psychotic symptoms
44
Antiandrogens
–
–
–
–
Gonadotropin release
inhibitors
Androgen Receptor
blockers
5a-reductase inhibitor
Androgen synthesis
inhibitors
45
Gonadotropin release inhibitors
• Long acting GnRH analogs
– Leuprolide
– Goserelin
– Nafarelin
46
Androgen Receptor blockers
• Nonsteroidal antiandrogens
– Flutamide
– Bicalutamide
• They block the action of dihydrotestosterone on
testosterone receptors and inhibit the synthesis of
new proteins in prostate and prostate cancer cells.
• Combined with GnRH analogs to treat inoperable
prostate Ca.
47
Androgen receptor blockers: Adverse
effects
•
•
•
•
Gynecomastia or nipple tenderness
Diarrhea
Hepatotoxicity
Impotence
48
5a-reductase inhibitor
• In the prostate, testosterone is converted into
dihydrotestosterone (DHT) by the action of 5areductase
• DHT acts on prostate cells to stimulate new growth
• Finastride: synthetic testosterone derivative
– It inhibits the synthesis of Dihydrotestosterone
(DHT) by inhibiting 5a-reductase
49
5a-reductase inhibitor
Therapeutic uses:
• Benign prostatic hyperplasia
• Male pattern baldness
50
Androgen synthesis inhibitors
• Ketoconazole:
– It is an antifungal agent.
– It inhibits gonadal & adrenal steroid synthesis by
inhibiting cholesterol side chain cleavage (inhibits
P450SCC).
Adverse effects:
– Gynecomastia
– hepatotoxicity
51
Hormones in cancer chemotherapy
Used as adjunctive therapy
Breast Ca
Prostate Ca
Anastrozole, Exemestane
Flutamide, Bicalutamide
Tamoxifen
Leuprolide, Goserelin
Leuprolide, Goserelin
Glucocorticoids
52

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