Female Sex Hormones (Estrogens and Progestins)

Nomenclature of Steroids
Number of Nuclear Positions and Steroid Classification
C H3
C H3
C H3
C H3
C-27 skeleton
… Cholestanes
C H3
C H3
C-19 skeleton
… Androstanes
C H3
C-24 skeleton
… Cholanes
C H3
C-18 skeleton
… Estranes
C H3
C-21 skeleton
… Pregnanes
Nomenclature of Steroids
Usage of ‘Nor’ terminology
C H3
C H3
C H3
C-27 skeleton
… Cholestanes
C H3
18-Nor C-27 skeleton
… 18-nor cholestane
C H3
C H3
C-19 skeleton
… Androstanes
19-Nor C-19 skeleton
… 19-nor androstane
Female Sex Hormones
(Estrogens and Progestins)
 Control:
 Follicle –Stimulating Hormone (FSH) stimulate the
production of Estrogens.
Luteinizing Hormone (LH) stimulate the production of
Progestins.
Estrogens
• Natural Estrogens:
OH
OH
O
OH
HO
HO
1 7 -estrad io l
E stron e
Excreted by human ovary
18
11
1 10
4
13
8
3
HO
OH
12 CH
3 17
9
2
5
7
6
HO
14
16
15
Excreted by human ovary.
It has 1/3 the effect of estradiol.
It is the metabolite by oxidation
of estradiol.
E striol
Physiological Effects
Uses
•
•
•
•
•
•
Birth control pills.
Failure of ovarian development.
Menstrual disturbances.
Suppress lactation after birth.
Postmenopausal osteoporosis.
Prostate cancer.
Side Effects
• Nausea, vomiting and diarrhea.
• Sodium and water retention.
• Inhibition of ovulation in large doses.
18
11
SAR
1 10
–
–
–
–
8
3
4
13
9
2
HO
OH
12 CH
3 17
5
14
16
15
7
6
Aromatic ring with C-3-OH is essential for activity.
Steroidal structures is not essential for activity.
Alkylation of the aromatic ring decrease the activity.
The 17-hydroxyl with constant distance from 3-OH is
essential for activity.
– The group between the two hydroxyl must be hydrophobic.
– Unsaturation of ring B decreases the activity.
– 17a- and 16 position when modified enhance the activity.
Steroidal Estrogenic Drugs
• Estradiol:
– Most active natural estrogen.
– Very short duration of action due to first pass metabolism.
– Mainly used for local effect on the uterus.
• Ethinyl estradiol (17-α-ethynylestradiol).
– 15- 20 more potent than estradiol orally.
OH
C
OH
HO
HO
1 7  -e stra d iol
Estra-1,3,5(10)triene-3,17-diol
E th in yl estrad iol
(S tertoid a l S em isyn th etic estrog en )
CH
Nonsteroidal Estrogens
• 1. Diethylstilbesterol:
– The trans form is the active one.
– Advantages:
•
•
•
•
As active as Estradiol.
Longer duration of action.
Orally active
Cheap.
OH
HO
Trans -diethylstilbene-4,4'-diol.
– Disadvantages:
• Increase the risk of uterine cancer.
– Uses:
4 .5 A
• Treatment of prostate cancer.
4 .5 A
OH
HO
HO
OH
CH3
Nonsteroidal Estrogens
2.Chlortrianisene:
Tris(p-anisyl)chloroethene.
Active orally
OMe
MeO
Cl
OMe
Xenoestrogens
(Enviromental Estrogens)
• Estrogenic compounds with weak activity present in food and
drinks.
• Isoflavones and coumestrol (Coumestan derivatives) present in
family Leguminosae are examples of xenoestrogens.
O
HO
OH
O
O
O
O
OH
G en isten
OH
C ou m esterol
Estrogen Antagonists
• Triphenylethylene antagonists:
– They are related to stilbene in structure.
– Antagonist bind strongly to the receptors.
• Aromatase inhibitors:
– Steroidal or nonsteroidal.
– Block conversion of androgens to estrogens.
• Uses: Treatment of estrogen dependent cancers.
Antiestrogens
Triphenylethylene antagonists
1.Clomiphene (clomid)
R
R = Cl
O
It acts as ovulation stimulant by
increasing gonadotrophin hormone (GRH).
50 mg dose for 5 days starting from 5th day of menstruation
If ovulation dose not occur, the dose is increased to 100 mg.
C H2C H3
C C N
H2 H2
C H2C H 3
2. Tamoxifen (Nolvadex):
R = CH3CH2-.
Used in treament of early & advanced breast cancer in postmenopausal
women.
12
Progestins
• Progesterone is the major natural progestin.
• Secretion: By the ovary mainly the corpus luteum during the
second half of the menstrual cycle.
• Physiological Effects:
–
–
–
–
Development of the endometrium.
Development of the mammary gland during pregnancy.
Milk secretion starts when its level decrease with birth.
Thermogenic action.
O
O
Preg-4-ene-3,20-dione.
O
SAR
O
– Steroidal nucleus essential for activity.
– Have some androgenic activity.
– Removal of the 19 CH3 increase activity.
– Unsaturation of ring B or C increase the activity.
– Removal of the keto function remove androgenic
activity.
Progestrogenic Drugs
• 1. Lynestrenol:
– Semisynthetic progestin with pure progestrogenic activity.
OH
O
C
O
P ro g estero n e
(N a tu ra l)
L y n estren o l
(S y n th etic)
CH
Uses:
•
•
•
•
•
•
•
Contraceptive pills.
Uterine bleeding.
Prevention of abortion.
Amenorrhea, dysmenorrhea, endometriosis.
Suppression of lactation.
Endometrial, renal and breast carcinoma.
Enhance respiration (for Hypoventilation).
Side Effects:
Nausea, vomiting, irregular bleeding, edema,
weight gain, breakthrough bleeding, breast
discomfort.
Progestrogenic Drugs
2. Medroxyprogestrone (provera)
17-α-acetoxy-6-α-methylpreg-4-ene-3,20-dione.
Uses: Oral contercetptive.
CH3
O
CH3
17
O
CH3
CH3
OC OCH3
Progestin Antagonists
• 1. Mifepristone:
– Compete with the progestin receptors.
– Uses:
• Contraceptive.
• Abortifacient.
CH3
N
OH
H3C
11-β-(p-dimethylaminophenyl)17-β-hydroxy-17-α-(1-propynyl)estra-4,9-diene-3-one.
CH3
O
CH3
Male Sex Hormones
(Androgens)
 Control:
 Luteinizing Hormone (LH) or Interstatial Cell-Stimulating
Hormones (ICSH) stimulate the production of Androgens.
Androgenic Steroids – Physiological Activities
Primarily two activities – Androgenic and Anabolic
Androgenic Activity
• Growth and development of male sex organs
• Important for male sex drive and performance
• Development of secondary sexual characteristics
• Important role in spermatogenesis
Anabolic Activity
• Development of muscle mass
• Reverse catabolic or tissue-depleting processes
Side Effects:
Sodium and water retention leads to edema.
Masculinization of women.
Hepatic dysfunction.
20
• Natural Androgens:
OH
O
OH
O
H
T esto stero n e
(N a tu ra l)
D ih y d ro testo stero n e
(N a tu ra l)
Structure Activity Relationships in Androgens
C H3 O H
C H3
Generalizations
O
•
Steroid skeleton is necessary
•
An electronegative (may not be oxygen) at 3 position is
required
•
A/B ring fusion should be either trans or presence of a
double bond at 4 position
•
Alkyl group (CH3) at 17a-position is necessary for anabolic
activity
•
22
Alkyl group at 17a- confers oral activity
Androgens & anabolic agents
1.Testosterone:
OH
17-β-hydroxy-androst-4-ene-3-one
CH3
In male:
FSH stimulates sperm production
LH stimulates secretion of testosterone.
CH3
O
Medical Uses:
1. Treatment of hypogonadism {decreased functional activity of the
gonads, thus resulting in lower amounts of testosterone}.
2. Androgens possess anabolic activity.
3. Treament of breast cancer in menopausal women.
4. Dysmenorrhea but of no advantage over Progestins & estrogens.
23
Adverse effects of testosterone
• Virilization (female)
• Feminizing side effects (male)
• Precocious puberty (i.e early puberty) &
•
•
•
•
•
stunted growth (reduced growth rate).
Cholestatic jaundice
Enlargement of prostate
Atherosclerosis
Hepatic carcinoma
Oedema
Androgenic Drugs
• 2. 17 a-methyltestosterone:
OH
CH3
(17-β-hydroxy-17-α-methyl-androst-4-ene-3-one)
– Orally active.
– Prolonged action.
– Androgenic and anabolic effects.
O
1 7 a -M eth y ltesto stero n e
(S em isy th etic)
* 3. Fluoxymestrone:
10 times more potent than testosterone.
OH
CH3
HO
CH3
F
O
CH3
Anabolic Steroids
• Class of steroid hormones related to the male
hormone – testosterone
• Increase protein synthesis within cells which
results in growth of muscle
• Also have androgenic properties which include
the development and maintenance of males
characteristics
• Have both medical and sport performance
uses
Anabolic Steroids
Anabolic Effects
• Two different, but overlapping
effects
• Anabolic – promote cell growth.
Increased protein synthesis,
appetite, bone remodeling and
growth, and production of red
blood cells
• Increase the size of muscle
fibers (hypertrophy) leading to
increase in muscle mass and
strength
• Decrease the amount of fat in
muscle
Anabolic Steroids
Androgenic Effects
• Androgenic (virilizing) - development and
maintenance of male characteristics:
• Increased growth of pubic, beard, chest and
limb hair
• Enlargement of vocal cords
• Suppression of natural sex hormones
Anabolic Steroids
Adverse Effects
• Most side effects are dose
dependent
• Elevated blood pressure
(most common)
• Increase LDL cholesterol
and decrease HDL
• Increase risk of CV disease
and coronary artery
disease, arrhythmias, and
heart attacks (chronic use)
Anabolic Steroids
Adverse Effects
• Accelerate the rate of premature
baldness (male and female)
• Acne – stimulates the sebaceous
glands
• Liver damage (cancer) –
increased demand on liver as
oral steroids are changed
(increase bioavailability and
stability)
Anabolic Steroids
Adverse Effects
•
•
•
•
•
Tendon rupture has been linked to AS
Stiffer and less elastic tendon
Probably tendon does not adapt as fast.
Gynecomastia – development of breast tissue in males
Conversion of testosterone to estrogen by an aromatase
enzyme
• Temporary infertility (decreased production of sperm)
• Testicular atrophy (caused by decrease levels in natural
testosterone)
Anabolic Steroids
Behavioral Effects
•
•
•
•
•
•
•
Controversial
Mood swings
Aggression (roid rage)
Mania
Depression
Withdrawal
Dependence
Anabolic Steroids
Medical Uses
•
•
•
•
•
•
•
Bone marrow stimulation – aplastic anemia
Growth stimulation – use GH now
Appetite stimulate – AIDS, cancer
Induction of male puberty – extreme delay
Reversible male contraceptive - future
Hormone replacement therapy (men)
Gender dysmorphia - psyciatric
Oral Anabolic Steroids
• 17-alpha methyl testosterone
(Android)
• 17-alpha ethyl testosterone
(Maxibolin)
• 1-methyl testosterone (Primobolan)
• Androstenediol (“Andro” food
supplements)
• Androstenedione
• Dihydroepiandrosterone (DHEA)
Injectable Anabolic Steroids
•
•
•
•
•
19-nortesterone ester derivitives (Durabolin)
Testosterone ester derivatives (Oreton)
Testosterone cypionate derivatives (Virilon)
Boldenone
Stanozolol (Winstrol) oral form as well
C H3 O H
Synthetic Anabolic Steroids:
C H3
1. Norethandrolone
O
Orally active.
Anabolic effects.
C-10 CH3 group removed eliminate androgenic effect.
2. Stanozolol
Orally active.
Anabolic effects.
OH
C 2H 5
C H3 O H
C H3
C H3
HN
N
36
O
H
Stanozolol
N o reth a n d ro lo n e
(S yth etic-P u re an ab olic)
Anabolic agents
3. Oxymetholone:
17-β-hydroxy-17-α-methyl-2-(hydroxymethylene)androstan-3-one.
OH
CH3 CH
3
CH3
H
C
HO
O
OH
CH3 CH
4. Oxandrolone:
17-β-hydroxy-17-α-methyloxandrostan-3-one
CH3
O
O
OH
CH3
5. Nandrolone: (nortestosterone)
Used as ester (decanoate or
phenylpropionate)
37
O
3
Structure Activity Relationships in Androgens
Anabolic
C H3 O H
Androgenic
C H3
Testosterone
(injectable)
O
1
1
Testosterone
1
esters (injectable)
1
C H3 O R
C H3
O
38
R = COCH2CH3
propionate
= CO(CH2)5CH3
enanthate
= COCH2CH2(C5H9) cypionate
Structure Activity Relationships in Androgens
Anabolic
C H3 O H
C H3
Androgenic
C H3
17a-methyl
Testosterone
(oral)
O
1
1
C H3 O H
HO
C H3
F
Fluoxymesterone
(oral)
1
1
O
C H3 O H
C H3
39
O
Structure Activity Relationships in Androgens
Anabolic
Androgenic
C H3 O H
H
Nandrolone
(injectable)
2.5
1
O
C H3 O H
C H3
C H3
HO
O
Oxymetholone
(oral)
2.5
1
H
C H3 O H
C H3
40
O
Structure Activity Relationships in Androgens
Anabolic
Androgenic
C H3 O H
C H3
C H3
HN
N
Stanozolol
(oral)
3
1
H
C H3 O H
C H3
H3C
O
C H3
Dromostanolone
(oral)
4
1
H
C H3 O H
C H3
41
O
Androgen Antagonists
• Androgen Receptor Antagonists:
1. Danazol
* Weak androgenic, anabolic, progestational & glucocorticoid action
2. Cyproterone acetate:
• Has antiandrogenic and progestrogenic activity.
• Used for treatment of acne, hirsutism, prostate hypertrophy, prostate
cancer and precocious puberty.
3. Flutamide:
• Non steroidal antiandrogen.
• Used for treatment of hirsutism and prostate cancer
4. 5a-Reductase inhibitors:
– They prevent conversion of testosterone into dihydrotestosterone.
– Used for treatment of Benign Prostatic Hyperplasia (BPH).
Androgens Antagonists
C H3
C H3
O
C H3 O H
C H3
CH
C H3
N
H
C H3
C H3
N
O
O
Danazol
(endometriosis)
N
H H
Finesteride (5 a reductase inhibitors)
(baldness)
O
C H3
HN
C H3
C F3
N O2
Cyproterone acetate
(prostate cancer)
43
Flutamide
(prostate cancer)
Male Contraceptives
• Gossypol:
– Is a phenolic compound present in cotton seed oil.
– Decrease number of sperms and impairs their motility.
– Its effect is reversible.
– Side Effects:
• Hypokalemia, weakness, diarrhea and edema.
1,25-Dihydroxy Vitamin D3
1,25-dihydroxy Vitamin D3 is also derived
from cholesterol and is lipid soluble
Not really a “vitamin” as it can be synthesized
de novo
Acts as a true hormone
Liver
Diet
OH
25-OHase
HO
HO
25(OH) D3
Vitamin D3
UV from
sunlight
Kidney
1-OHase
Skin
OH
HO
7
Provitamin D3
(7-dehydrocholesterol:
Intermediate in cholesterol
synthesis)
OHase =
hydroxylase
HO
OH
1,25(OH)2 D3
(active hormone form)
Photobiosynthesis of vitamin D3 and its metabolism
Specific receptors in
intestine, bone, kidney
Ca:
Intestinal absorption
Renal reabsorption
PO4:
Intestinal absorption
Renal reabsorption
The hormonal interactions controlling
bone mineral homeostasis
Actions of Vitamin D on Gut, Bone, and Kidney
Intestine
Vitamin D
Increased calcium and phosphate absorption by 1,25
(OH)2D
Kidney
Calcium and phosphate excretion may be decreased by
25(OH)D and 1,25(OH)2D1
Bone
Increased calcium and phosphate resorption by
1,25(OH)2D; bone formation may be increased by
1,25(OH)2D and 24,25(OH)2D
Net effect on serum Serum calcium and phosphate both increased
levels
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