Download can - LSU School of Medicine

Estrogens, Progestins and Androgens
Becky Worthylake
[email protected]
Outline
• Overview
• Estrogens – General
• Estrogens & Modifiers – Therapeutic Formulations & Uses
• Progestins – Therapeutic Formulations & Uses
• Contraception
• Androgens – General
• Androgens – Uses & Therapeutic Formulations
Overview: Endocrine Physiology
Hypothalamus (GnRH)
& Pitutary
Luteinizing Hormone &
Follicle Stimulating Hormone
Ovaries & Testes
Reproduction
Overview: Molecular Mechanisms
Overview: Molecular Mechanisms
Outline
• Estrogens – General
• Synthesis
• Physiology
• Regulation
Synthesis
21
CH 3
Cholesterol
1
2
3
OH
A
4
11
19
CH 3
9
10
B
20
18 CH
12 CH 3
17
13
D
C
14
24
28
22
CH
2
CH 3
CH 2
CH 2
CH 2 25
23
CH 3
16
27
15
8
7
5
6
Pregnenolone
Progesterone
DHEA
Androstenedione
Androstenedione
Testosterone
OH
aromatase
OH
Estradiol
Physiology
Reproductive Tissues
Growth of
endometrium
Growth of
Vaginal
Epithelium
Ovarian
follilcle
Sperm
transport
Lowers
Plasma cholesterol
ESTROGENS
Behavioral effects
Liver synthesis of
Transport Proteins
Mammary
Gland
Decreases
rate of bone
resorption
Reduces
Bowel motility
Increases blood coagulability
Non-reproductive Tissues
Maintains normal
skin structure
Regulation: Feeback Loops
FSH, LH
Same a
Different b
Regulation : Circulating Levels
Regulation: Impact on Reproductive Tissues
Follicular
Plasma Level
0
4
8
Luteal
Days
12
16
Ovulation
20
24
28
32
Progesterone
Estradiol
Basal Body
Temperature
oF
Vaginal
Cornification
Cervical
Mucus
Elasticity
Glycogen Vacuoles
Endometrium
Menses
Proliferative
Phase
Secretory
Phase
Menses
Outline
• Estrogens & Estrogen Modifiers – Therapeutic Formulations and Uses
• Therapeutic Estrogens
• SERMs (selective estrogen receptor modulators)
• Estrogen Synthesis Inhibitors
Therapeutic Estrogens
DRUG
Estradiol
COMMENTS
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)
Indications
• Primary Hypogonadism
• Postmenopausal Hormonal Therapy
• Oral Contraceptives
• Suppress ovulation in patients with intractable dysmenorrhea or hirsutism
• Fertility treatments
Therapeutic Estrogens Cont’
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
Uses: HRT – Symptoms of Menopause
 LH, FSH
Estrone is major Estrogen
Postmenopausal
Normal
HDL/LDL ratio
GnRH
GnRH
Normal, Midcycle
Hot Flashes
Uses : HRT – Effects of Treatment
(Increased risk of MI and stroke, especially in
the first year)
Uses: HRT - Formulations
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.
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
SERMs: Tamoxifen continued
- 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: Other
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
Anti-Estrogens
• 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
Estrogen Synthesis Inhibitors
•
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
Outline
• Progestins – Therapeutic Formulations & Uses
• Therapeutic Progestins
• anti-Progesterones
Progestins – Therapeutic Progesterone
• 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 continued
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: 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
Contraception
Hypothalamus
Oral Contraceptives
GnRH analogs
GnRH
Pituitary
LH
FSH
Ovary
ovum
Tubal Ligation
IUD
Progestin only contraceptive
Barrier Methods
Natural family planning
Estradiol
Progesterone
Fallopian Tube
Ovum transport
Uterus
Implantation
Sperm transport
Cervix and Vagina
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 Estrogens
1. Estrogens: mestranol and ethinyl estradiol
• 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
Hepatic Metabolism
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/antiestrogenic actions. Rapidly absorbed (Norethindrone)
OH
OH
C
H
H
H
H
O
O
AC
C CH
H
H
O
H
19-NORTESTOSTERONE
H
AC
NORETHINDRONE
H
O
ETHYNODIOL DIACETATE
CH
Contraception: Therapuetic Progestins cont’
OH
H3C
• Gonanes: More potent than estranes and less androgenic
activity and are now used in the 3rd generation
combination oral contraceptives
(Norgestrel, Norgestimate, Desogestrel)
CH2
C
H
H
H
O
NORGESTREL
OH
H3C
CH2
H2C
C
CH
H3C
OCOCH3
C CH
CH2
H
H
H
H
H
O
H
HON
DESOGESTREL
NORGESTIMATE
CH
Therapeutic Estrogen & Progestin Combinations
• 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
Contraception: Formulations
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 ORTHONOVUM 1/35, NORDETTE, ORTHO-CEPT ,
LOESTRIN)
Contraception: Formulations
Biphasics:
•
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.
Contraception: Formulations
Triphasic:
• 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
Contraception: Formulations
Progestin Only:
• Oral formulations of norethindrone (micronor) or levonorgestrel (ovrette)
taken daily
• Subdermal implants of levonorgestrel (norplant) for slow-release and longterm 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).
Emergency Contraceptives
• 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)
Extended Regimen Contraception
Levonorgestrel / ethinyl estradiol 0.15 mg / 0.03 mg
And either placebo or ethinyl estradiol tablets 0.01 mg tablets)
Brand Names: Jolessa, Quasense, Seasonale, Seasonique
91-day courses of tablets
Advantages
• Period once every 3 months
• Period last about 3 days with decreased bleeding ,
Side Effects: Breakthrough bleeding and spotting
Seasonique: incorporates low-dose estrogen rather than placebo tablets in
an effort to limit bloating, hormonal fluctuations, and breakthrough
bleeding.
Contraceptives: MOA
LH/FSH release
 Follicular
development &
ovulation
Contraceptives: MOA
Progestin only:
• Thick cervical mucus
• Implantation of blastocyst in endometrium
• Contractions of uterus & F.tubes are modified
Effects: Benefits
Initiating Method
• 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
Other Beneficial effects
1.
2.
3.
4.
5.
Decreases Dysmenorrhea
Decreases benign breast and ovarian cysts
Regulates cycle in anovulatory women
Decreased blood loss during menstruation
50% reduction in ovarian and endometrial cancer.
Effects: Drug Interactions
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. anticoagulants
b. benzodiazepines,
c. beta-blockers
d. corticosteroids, and tricyclic antidepressants
Effects: Contraindications
1.
Absolute
a. History of thromboembolism, MI, stroke
b. Impaired liver function
c. Known or suspected breast cancer
d. Undiagnosed abnormal vaginal bleeding
e. Known or suspected pregnancy
f. Smokers over age 35 (may use progestin-only)
2. Relative
a. – Migraine headaches
b. – Hypertension - ok if <35, or healthy, or BP controlled
c. – Elective surgery: Discontinue 4wks. prior to major surgery
d. – Gallstones/ Cholecystitis
e. – Epilepsy: anti-seizure meds may decrease effectiveness of OCP’s
f. – Diabetes: small risk or worsening vascular disease.
Outline
• Androgens – General
• Synthesis
• Regulation
• Physiological Effects
Androgens : Synthesis
CHOLESTEROL
NADPH
P450scc
LH
Pregnenolone
Progesterone
Dehydroepiandrosterone
(DHEA)
Testosterone
5a-Reductase
Dihydrotestosterone
(DHT)
Aromatase
Estradiol
FSH
Androgens : Regulation
Androgens : Regulation
Plasma Testosterone
conjugating
enzymes
Conjugate s
liver, kidney
5 a-reductase
arom atas e
Te stoste rone
testes, pituitary,
muscle
Dihydrote stoste rone
prostate, scrotum,
penis, bone
17 b-dehydrogenase
Estradiol
fat, liver, CNS,
skin, hair
Biologically Active
17 ke toste roids
liver, kidney
Excretory Metabolites
•Circulating testosterone
and dihydrotestosterone
*Circulating
testosteroe
and dihydrotestosteron
e
1-2 % - free
1-2% Free- bound to SSBG -- (sex steroid binding
65%
65% bound to SSBG
(sex steroid binding globulin)
globulin)
33-34% bound
to albumin
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 : Physiology
External
Genitalia
Puberty
Beard
Growth
Prostate
Larynx
Fetal
Epididymus
Vas deferens
Seminal vesicles
DHT
E2
DHT
E
Penis
(-)
PIT
DHT
Testosterone
DHT
DHT
E
E
Sperm
Production
Sperm
Production
ADULT
Increased
Ephyiseal
Closure
Muscle
Upper
Body
Fat
VLDL
HDL
LDL
Sex drive
behavior
Outline
• Androgens – Uses & Therapeutics
• Treatable Conditions
• Therapeutic Formulations of Testosterones and Androgens
• Androgen Antagonists
Treatable Conditions
A.
Male hypogonadism: develop or maintain secondary sex characteristics
B.
Andropause
C.
Prostate Cancer
D.
Male Pattern Baldness
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 esters
Monitoring 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
Theraputic Formulations: Testosterones
Testosterone (HISTERONE)
• oral admin. leads to absorption into the hepatic circulation
and rapid catabolism
• Effective in transdermal patches
Testosterone derivatives
•17-a-alkylated androgens: decreased breakdown by liver,
•but can elicit hepatic toxicity
Theraputic Formulations: Androgens
17aHydroxyl Group Esters
• More lipophilic than testosterone
• Converted to testosterone in the circulation
Testosterone propionate (Neo-Hombreol®)
• Short duration of action (i.e. 1-2 days) even when
delivered IM
Testosterone enanthate (Delatestryl®)
• Given IM once every two weeks
Testosterone undecanoate (Andriol®)
• Absorbed into lymphatic system when taken
orally (40 mg capsules)
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: Side Effects
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)
Anabolic Steroid and Androgen Abuse in Sports
100-200 x normal daily production in men
Androgen Antagonists
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)