Very good power point presentation

1. Estrogens, Progestins and Androgens
Becky Worthylake
bworth@lsuhsc.edu

2. Outline
• Overview
• Estrogens – General
• Estrogens & Modifiers – Therapeutic Formulations & Uses
• Progestins – Therapeutic Formulations & Uses
• Contraception
• Androgens – General
• Androgens – Uses & Therapeutic Formulations

3. Hypothalamus (GnRH)
& Pitutary
Luteinizing Hormone &
Follicle Stimulating Hormone
Ovaries & Testes
Reproduction
Overview: Endocrine Physiology

4. Overview: Molecular Mechanisms

5. Overview: Molecular Mechanisms

6. Outline
• Estrogens – General
• Synthesis
• Physiology
• Regulation

7. Cholesterol
Pregnenolone
Estradiol
OH
OH
OH
A B
C D
1
2
3
4
5
6
7
8
9
10
CH 3
11
19
12
13
14
15
16
17
18
CH 3
CH 2
CH 3
CH
CH 2
CH 2 CH 2
CH 3
CH 3
20
21
23
22
24
25
27
28
Testosterone
DHEA
Androstenedione
Progesterone
Androstenedione
aromatase
Synthesis

8. Growth of
Epithelium
rate of bone
skin structure
Liver synthesis of
follilcle
Growth 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

9. FSH, LH
Same a
Different b
Regulation: Feeback Loops

10. Regulation : Circulating Levels

11. 0 4 8 12 16 20 24 28 32
Days
Plasma
Level Estradiol
Progesterone
Ovulation
oF
Basal Body
Temperature
Cervical
Mucus
Elasticity
Vaginal
Cornification
Endometrium
Glycogen Vacuoles
M enses M enses
Proliferative
Phase
Secretory
Phase
Follicular Luteal
Regulation: Impact on Reproductive Tissues

12. Outline
• Estrogens & Estrogen Modifiers – Therapeutic Formulations and Uses
• Therapeutic Estrogens
• SERMs (selective estrogen receptor modulators)
• Estrogen Synthesis Inhibitors

13. 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)

14. 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’

15. Uses: HRT – Symptoms of Menopause
 LH, FSH
Estrone is major Estrogen
GnRH
Normal, Midcycle
Normal
Postmenopausal
GnRH
Hot Flashes
HDL/LDL ratio

16. (Increased risk of MI and stroke, especially in
the first year)
Uses : HRT – Effects of Treatment

17. 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

18. 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

19. SERMs: Tamoxifen – Breast Cancer
2-3 fold increased risk
of deep vein
thrombosis &
pulmonary embolism

20. - 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

21. 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

22. • 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

23. • 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

24. • Progestins – Therapeutic Formulations & Uses
• Therapeutic Progestins
• anti-Progesterones
Outline

25. • 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

26. 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

27. 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)

28. Outline
• Contraception
• Therapeutic Estrogens & Progesterones
• Oral Contraceptive Formulations
• Emergency Contraception
• Extended-Regimen Contraception
• Mechanism of Action
• Effects

29. Hypothalamus
Pituitary
Ovary
Uterus
Cervix and Vagina
LH FSH
GnRH
Oral Contraceptives
GnRH analogs
Fallopian Tube
ovum
Estradiol
Progesterone
Sperm transport
Ovum transport
Implantation
Tubal Ligation
IUD
Progestin only contraceptive
Barrier Methods
Natural family planning
Contraception

30. 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)

31. Contraception: Therapeutic Estrogens
1. 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

32. OH
O
H
H
H
19-NORTESTOSTERONE
OH
C CH
O
H
H
H
NORETHINDRONE
O
C CH
O
H
H
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)

33. OH
CH2 C CH
O
H3C
H
H
H
DESOGESTREL
OCOCH3
CH2 C CH
HON
H3C
H
H
H
NORGESTIMATE
OH
CH2 C CH
O
H3C
H
H
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’

34. • 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

35. 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

36. • 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

37. • 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

38. • 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:

39. • 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

40. 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 mg
And 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

41. Contraceptives: MOA
LH/FSH release
 Follicular
development &
ovulation

42. Progestin only:
• Thick cervical mucus
• Implantation of blastocyst in endometrium
• Contractions of uterus & F.tubes are modified
Contraceptives: MOA

43. • 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 Dysmenorrhea
2. Decreases benign breast and ovarian cysts
3. Regulates cycle in anovulatory women
4. Decreased blood loss during menstruation
5. 50% reduction in ovarian and endometrial cancer.
Effects: Benefits

44. 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: Drug Interactions

45. 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.
Effects: Contraindications

46. Outline
• Androgens – General
• Synthesis
• Regulation
• Physiological Effects

47. CHOLESTEROL
Pregnenolone
Progesterone Dehydroepiandrosterone
(DHEA)
Testosterone
P450scc
NADPH
FSH
Aromatase
5a-Reductase
Estradiol
Dihydrotestosterone
(DHT)
LH
Androgens : Synthesis

48. Androgens : Regulation

49. Plasma Testosterone
5 a-reductase
conjugating
enzymes
Testosterone
testes, pituitary,
muscle
Estradiol
fat, liver, CNS,
skin, hair
17 b-dehydrogenase
Conjugates
liver, kidney
17 ketosteroids
liver, kidney
Excretory Metabolites
Dihydrotestosterone
prostate, scrotum,
penis, bone
Biologically Active
aromatase
*Circulating testosteroe and dihydrotestosteron
e
1-2 % - free
65% - 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% Free
65% bound to SSBG (sex steroid binding globulin)
33-34% bound to albumin

50. Testosterone
DHT
Larynx
VLDL
HDL
LDL
DHT
DHT
E2
Beard
Growth
Prostate
Penis
Puberty Fetal
Epididymus
Vas deferens
Seminal vesicles
External
Genitalia
E
Muscle Upper
Body
Fat
Ephyiseal
Closure
Sperm
Production
ADULT
DHT
E
Increased
PIT
(-)
Sperm
Production
Sex drive
behavior
DHT
E
Androgens : Physiology

51. Outline
• Androgens – Uses & Therapeutics
• Treatable Conditions
• Therapeutic Formulations of Testosterones and Androgens
• Androgen Antagonists

52. A. Male hypogonadism: develop or maintain secondary sex characteristics
B. Andropause
C. Prostate Cancer
D. Male Pattern Baldness
Treatable Conditions

53. 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

54. 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

55. •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

56. 17aHydroxyl 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

57. 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

58. 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

59. 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