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Estrogens, Progestins and Androgens. Becky Worthylake [email protected]. Outline. Overview Estrogens – General Estrogens & Modifiers – Therapeutic Formulations & Uses Progestins – Therapeutic Formulations & Uses Contraception Androgens – General - PowerPoint PPT Presentation
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Estrogens, Progestins and Androgens
Becky [email protected]
Outline
• Overview
• Estrogens – General
• Estrogens & Modifiers – Therapeutic Formulations & Uses
• Progestins – Therapeutic Formulations & Uses
• Contraception
• Androgens – General
• Androgens – Uses & Therapeutic Formulations
Hypothalamus (GnRH)& Pitutary
Luteinizing Hormone &Follicle Stimulating Hormone
Ovaries & Testes
Reproduction
Overview: Endocrine Physiology
Overview: Molecular Mechanisms
Overview: Molecular Mechanisms
Outline
• Estrogens – General
• Synthesis
• Physiology
• Regulation
Cholesterol
Pregnenolone
Estradiol
OH
OH
OH
A B
C D1
2
3
45
6
7
89
10
CH 3
1119
12
13
1415
1617
18CH 3
CH 2CH 3CH
CH 2
CH 2 CH 2
CH 3
CH 32021
23
2224
25
27
28
Testosterone
DHEA
Androstenedione
Progesterone
Androstenedione
aromatase
Synthesis
Growth of
Epithelium
rate of bone
skin structure
Liver synthesis of
follilcleGrowth of endometrium
Lowers Plasma cholesterol
Behavioral effects
ESTROGENS
Reproductive Tissues
Vaginal Mammary Gland
Decreases
resorption
Increases blood coagulability Maintains normal
Reduces Bowel motility
Sperm transport
Transport Proteins
Ovarian
Non-reproductive Tissues
Physiology
1. Estrogen exerts both negative and positive feedback.
2. Gonadal hormones act on both the anterior pituitary and the hypotalamus.
TAKE HOME POINTS:
3. Higher brian centers influence the release of GnRH from the hypothalamic neurons
STRESS
visual
HYPOTHALAMUS
GnRH
GonadotrophsLH, FSH
LongLoop
LongLoopLH
FSH
pinealolfactory
Estrogen
Estrogen(+/-)
Progesterone ovary
LongLoop
Estrogen(+/-)
FSH, LHSame aDifferent b
Regulation: Feeback Loops
-12 -10-8 -6 -4 -2 0 2 4 6 8 1012 14MensesMenses
Menses
Ovulation
Follicular Growth Corpus Luteum
48
1216202428323640
60
80
LH
and
FSH
(m
U/m
l )
Prog Estradiol
10
8
67
9
54321
1.00.90.80.70.60.50.40.30.20.1
(ng / ml)P
E
E
FSH
F
LHRegulation : Circulating Levels
0 4 8 12 16 20 24 28 32Days
Plas
ma
Leve
lEstradiol
ProgesteroneOvulation
oF
Basal BodyTemperature
Cervical MucusElasticity
Vaginal Cornification
Endometrium
Glycogen Vacuoles
Menses MensesProliferative Phase
SecretoryPhase
Follicular LutealRegulation: Impact on Reproductive Tissues
Outline
• Estrogens & Estrogen Modifiers – Therapeutic Formulations and Uses
• Therapeutic Estrogens
• SERMs (selective estrogen receptor modulators)
• Estrogen Synthesis Inhibitors
Therapeutic Estrogens
Indications• Primary Hypogonadism• Postmenopausal Hormonal Therapy• Oral Contraceptives • Suppress ovulation in patients with intractable dysmenorrhea or hirsutism• Fertility treatments
DRUG COMMENTS
Estradiol 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)
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
Therapeutic Estrogens Cont’
Uses: HRT – Symptoms of Menopause
LH, FSH
Estrone is major Estrogen
GnR
H
Normal, Midcycle
Normal
Postmenopausal
GnR
H
Hot FlashesHDL/LDL ratio
(Increased risk of MI and stroke, especially in the first year)
Uses : HRT – Effects of Treatment
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.
Uses: HRT - Formulations
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
- 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: Tamoxifen continued
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
SERMs: Other
• 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
Anti-Estrogens
• 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
Estrogen Synthesis Inhibitors
• Progestins – Therapeutic Formulations & Uses
• Therapeutic Progestins
• anti-Progesterones
Outline
• 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 – Therapeutic Progesterone
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 continued
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
Hypothalamus
Pituitary
Ovary
Uterus
Cervix and Vagina
LH FSH
GnRHOral ContraceptivesGnRH analogs
Fallopian Tube
ovum EstradiolProgesterone
Sperm transport
Ovum transport
Implantation
Tubal Ligation
IUDProgestin only contraceptive
Barrier MethodsNatural family planning
Contraception
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 Estrogens1. Estrogens: mestranol and ethinyl estradiol
Hepatic Metabolism
• 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
OH
O
HH
H
19-NORTESTOSTERONE
OHC CH
O
HH
H
NORETHINDRONE
OC CH
O
HH
H
ETHYNODIOL DIACETATE
AC
AC
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/anti- estrogenic actions. Rapidly absorbed (Norethindrone)
OHCH2 C CH
O
H3C
HH
H
DESOGESTREL
OCOCH3CH2 C CH
HON
H3C
HH
H
NORGESTIMATE
OHCH2 C CH
O
H3C
HH
H
NORGESTREL
H2C
• Gonanes: More potent than estranes and less androgenic activity and are now used in the 3rd generation combination oral contraceptives
(Norgestrel, Norgestimate, Desogestrel)
Contraception: Therapuetic Progestins cont’
• 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
Therapeutic Estrogen & Progestin Combinations
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 ORTHO-NOVUM 1/35, NORDETTE, ORTHO-CEPT , LOESTRIN)
Contraception: Formulations
• 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.
Biphasics:
Contraception: Formulations
• 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
Triphasic:
Contraception: Formulations
• Oral formulations of norethindrone (micronor) or levonorgestrel (ovrette) taken daily
• Subdermal implants of levonorgestrel (norplant) for slow-release and long-term 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).
Contraception: Formulations
Progestin Only:
• 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)
Emergency Contraceptives
Advantages • Period once every 3 months• Period last about 3 days with decreased bleeding ,
Side Effects: Breakthrough bleeding and spotting
Levonorgestrel / ethinyl estradiol 0.15 mg / 0.03 mgAnd either placebo or ethinyl estradiol tablets 0.01 mg tablets) Brand Names: Jolessa, Quasense, Seasonale, Seasonique
91-day courses of tablets
Seasonique: incorporates low-dose estrogen rather than placebo tablets in an effort to limit bloating, hormonal fluctuations, and breakthrough bleeding.
Extended Regimen Contraception
Contraceptives: MOA
LH/FSH release
Follicular development & ovulation
SPERM Transport
EGG Transport
Progestin only:• Thick cervical mucus• Implantation of blastocyst in endometrium• Contractions of uterus & F.tubes are modified
Contraceptives: MOA
• 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
Initiating Method
Other Beneficial effects
1. Decreases Dysmenorrhea2. Decreases benign breast and ovarian cysts3. Regulates cycle in anovulatory women4. Decreased blood loss during menstruation5. 50% reduction in ovarian and endometrial cancer.
Effects: Benefits
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. anticoagulantsb. benzodiazepines, c. beta-blockersd. corticosteroids, and tricyclic antidepressants
Effects: Drug Interactions
1. Absolute
a. History of thromboembolism, MI, strokeb. Impaired liver functionc. Known or suspected breast cancerd. Undiagnosed abnormal vaginal bleedinge. Known or suspected pregnancy f. Smokers over age 35 (may use progestin-only)
2. Relative
a. – Migraine headachesb. – Hypertension - ok if <35, or healthy, or BP controlledc. – Elective surgery: Discontinue 4wks. prior to major surgeryd. – Gallstones/ Cholecystitise. – Epilepsy: anti-seizure meds may decrease effectiveness of OCP’sf. – Diabetes: small risk or worsening vascular disease.
Effects: Contraindications
Outline
• Androgens – General
• Synthesis
• Regulation
• Physiological Effects
CHOLESTEROL
Pregnenolone
Progesterone Dehydroepiandrosterone(DHEA)
Testosterone
P450sccNADPH
FSHAromatase5a-Reductase
EstradiolDihydrotestosterone(DHT)
LH
Androgens : Synthesis
Androgens : Regulation
Plasma Testosterone
5 a-reductase
conjugating enzymes
Testosteronetestes, pituitary, muscle
Estradiol fat, liver, CNS, skin, hair
17 b-dehydrogenase
Conjugatesliver, kidney
17 ketosteroidsliver, kidney
Excretory Metabolites
Dihydrotestosteroneprostate, scrotum, penis, bone
Biologically Active
aromatase
*Circulating testosteroe and dihydrotestosterone1-2 % - free65% - bound to SSBG -- (sex steroid binding
globulin)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 : Regulation
• Circulating testosterone and dihydrotestosterone
1-2% Free65% bound to SSBG (sex steroid binding globulin)33-34% bound to albumin
Testosterone
DHTLarynx
VLDL
HDL
LDL
DHT
DHT
E2Beard Growth
Prostate
Penis
Puberty FetalEpididymusVas deferens
Seminal vesicles
ExternalGenitalia
E
Muscle UpperBodyFat
Ephyiseal Closure
Sperm Production
ADULT
DHT
E
Increased
PIT(-)
Sperm Production
Sex drivebehavior
DHT
E
Androgens : Physiology
Outline
• Androgens – Uses & Therapeutics
• Treatable Conditions
• Therapeutic Formulations of Testosterones and Androgens
• Androgen Antagonists
A. Male hypogonadism: develop or maintain secondary sex characteristics
B. Andropause
C. Prostate Cancer
D. Male Pattern Baldness
Treatable Conditions
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 estersMonitoring 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
• 17-a-alkylated androgens: decreased breakdown by liver, • but can elicit hepatic toxicity
Testosterone derivatives
Testosterone (HISTERONE) • oral admin. leads to absorption into the hepatic circulation
and rapid catabolism • Effective in transdermal patches
Theraputic Formulations: Testosterones
17aHydroxyl Group Esters• More lipophilic than testosterone• Converted to testosterone in the circulation
Testosterone enanthate (Delatestryl®)• Given IM once every two weeks
Testosterone undecanoate (Andriol®)• Absorbed into lymphatic system when
taken orally (40 mg capsules)
Testosterone propionate (Neo-Hombreol®)• Short duration of action (i.e. 1-2 days) even when
delivered IM
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: Androgens
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)
Theraputic Formulations: Side Effects
Anabolic Steroid and Androgen Abuse in Sports 100-200 x normal daily production in men
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)
Androgen Antagonists