Nomenclature of Steroids
Number of Nuclear Positions and Steroid Classification
CH
3
CH
3
CH
3
CH
3
CH
3
CH
3
C-27 skeleton
… Cholestanes
CH
3
CH
3
C-24 skeleton
… Cholanes
CH
3
C-21 skeleton
… Pregnanes
C-19 skeleton
… Androstanes
C-18 skeleton
… Estranes

Nomenclature of Steroids
Usage of ‘Nor’ terminology
CH
3
CH
3
CH
3
C-27 skeleton
… Cholestanes
CH
3
CH
3
18-Nor C-27 skeleton
… 18-nor cholestane
CH
3
C-19 skeleton
… Androstanes
19-Nor C-19 skeleton
… 19-nor androstane

 Control:

Follicle –Stimulating Hormone (FSH) stimulate the production of Estrogens.
 Luteinizing Hormone (LH) stimulate the production of
Progestins.

• Natural Estrogens:
OH
O
HO
17

-estradiol
Excreted by human ovary
HO
HO
Estrone
Excreted by human ovary.
It has 1/3 the effect of estradiol.
It is the metabolite by oxidation of estradiol.
H O
2
3
1
4
11
10
5
6
12
18
OH
CH
3
17
16
9
13
15
8
14
7
Estriol
OH
OH

• Birth control pills.
• Failure of ovarian development.
• Menstrual disturbances.
• Suppress lactation after birth.
• Postmenopausal osteoporosis.
• Prostate cancer.
• Nausea, vomiting and diarrhea.
• Sodium and water retention.
• Inhibition of ovulation in large doses.

SAR
H O
2
3
1
4
11
10
5
6
12
18
OH
CH
3
17
16
9
13
15
8
14
7
– 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.
– 17 a
- and 16 position when modified enhance the activity.

• 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 OH
C CH
HO
17

-estradiol
Estra-1,3,5(10)triene-3,17-diol
HO
Ethinyl estradiol
(Stertoidal Semisynthetic estrogen)

• 1. Diethylstilbesterol:
– The trans form is the active one.
– Advantages:
• As active as Estradiol.
• Longer duration of action.
• Orally active
• Cheap.
HO
Trans -diethylstilbene-4,4'-diol.
– Disadvantages:
• Increase the risk of uterine cancer.
– Uses:
• Treatment of prostate cancer.
4.5A
OH
4.5A
H O
H O
OH
OH
CH
3

2.Chlortrianisene:
Tris(p-anisyl)chloroethene.
Active orally
OMe
MeO
Cl
OMe

(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
O
O
OH O
Genisten
OH
O
Coumesterol
OH

• 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.
Treatment of estrogen dependent cancers.

Triphenylethylene antagonists
1.Clomiphene (clomid)
R = Cl
It acts as ovulation stimulant by increasing gonadotrophin hormone (GRH).
R
O C
H
2
50 mg dose for 5 days starting from 5 th day of menstruation
If ovulation dose not occur, the dose is increased to 100 mg.
C
H
2
N
CH
2
CH
3
CH
2
CH
3
2. Tamoxifen (Nolvadex):
R = CH
3
CH
2
-.
Used in treament of early & advanced breast cancer in postmenopausal women.
12

• 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.

SAR
O
– Steroidal nucleus essential for activity.
– Have some androgenic activity.
– Removal of the 19 CH
3 increase activity.
– Unsaturation of ring B or C increase the activity.
– Removal of the keto function remove androgenic activity.
O

• 1. Lynestrenol:
– Semisynthetic progestin with pure progestrogenic activity.
O OH
C CH
O
Progesterone
(Natural)
Lynestrenol
(Synthetic)

• Contraceptive pills.
• Uterine bleeding.
• Prevention of abortion.
• Amenorrhea, dysmenorrhea, endometriosis.
• Suppression of lactation.
• Endometrial, renal and breast carcinoma.
• Enhance respiration (for Hypoventilation).
Nausea, vomiting, irregular bleeding, edema, weight gain, breakthrough bleeding, breast discomfort.

2. Medroxyprogestrone (provera)
17-α-acetoxy-6-α-methylpreg-4-ene-3,20-dione.
Uses: Oral contercetptive.
O
CH
3
CH
3
OCOCH
3
CH
3
O
CH
3
17

• 1. Mifepristone:
– Compete with the progestin receptors.
– Uses:
• Contraceptive.
• Abortifacient.
CH
3
N
H
3
C
CH
OH
3
11β -(p-dimethylaminophenyl)-
17β -hydroxy-17α -(1-propynyl)estra-4,9-diene-3-one.
O
CH
3

(Androgens)
 Control:
 Luteinizing Hormone (LH) or Interstatial Cell-Stimulating
Hormones (ICSH) stimulate the production of Androgens.

20
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.

• Natural Androgens:
OH
O
Testosterone
(Natural)
O
H
Dihydrotestosterone
(Natural)
OH

Structure Activity Relationships in Androgens
CH
3
OH
CH
3
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 (CH
3
) at 17 a -position is necessary for anabolic activity
• Alkyl group at 17 a - confers oral activity
22

1.Testosterone:
17-β-hydroxy-androst-4-ene-3-one
CH
OH
3
In male:
FSH stimulates sperm production
LH stimulates secretion of testosterone.
CH
3
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:
(17-β-hydroxy-17-α-methyl-androst-4-ene-3-one )
– Orally active.
– Prolonged action.
– Androgenic and anabolic effects.
O
OH
CH
3
17 a
-Methyltestosterone
(Semisythetic)
* 3. Fluoxymestrone:
10 times more potent than testosterone.
CH
OH
3
CH
3
H O
CH
3
F
O

• 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

• 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

• 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

• 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)

• 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)

• 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)

• Controversial
• Mood swings
• Aggression (roid rage)
• Mania
• Depression
• Withdrawal
• Dependence

• 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

• 17-alpha methyl testosterone
(Android)
• 17-alpha ethyl testosterone
(Maxibolin)
• 1-methyl testosterone (Primobolan)
• Androstenediol (“Andro” food supplements)
• Androstenedione
• Dihydroepiandrosterone (DHEA)

• 19-nortesterone ester derivitives (Durabolin)
• Testosterone ester derivatives (Oreton)
• Testosterone cypionate derivatives (Virilon)
• Boldenone
• Stanozolol (Winstrol) oral form as well

Synthetic Anabolic Steroids:
CH
3
1. Norethandrolone
Orally active.
O
Anabolic effects.
C-10 CH
3 group removed eliminate androgenic effect.
CH
3
OH
2. Stanozolol
Orally active.
Anabolic effects.
OH
C
2
H
5 CH
3
OH
CH
3
CH
3
H N
N
O
H
Norethandrolone
(Sythetic-Pure anabolic)
36
Stanozolol

Anabolic agents
3. Oxymetholone:
17-β-hydroxy-17-α-methyl-2-(hydroxymethylene)androstan-3-one.
H O
H
C
O
CH
3
CH
OH
3
CH
3
4. Oxandrolone:
17-β-hydroxy-17-α-methyloxandrostan-3-one
O
O
5. Nandrolone: (nortestosterone)
Used as ester (decanoate or phenylpropionate)
37
O
CH
3
CH
OH
3
CH
3
OH
CH
3

38
O
Structure Activity Relationships in Androgens
CH
3
OH
Anabolic Androgenic
CH
3
Testosterone 1 1
(injectable)
O
CH
3
OR
CH
3
Testosterone 1 1
esters (injectable)
R = COCH
2
= CO(CH
= COCH
CH
3
2
)
5
2
CH
CH
2
(C
3
5
H propionate enanthate
9
) cypionate

O
Structure Activity Relationships in Androgens
CH
3
CH
3
OH
CH
3
Anabolic Androgenic
17 a -methyl
Testosterone 1 1
(oral)
39
O
H O
CH
3
F
CH
3
OH
Fluoxymesterone 1 1
(oral)
CH
3
CH
3
OH
O

O
Structure Activity Relationships in Androgens
Anabolic Androgenic
CH
3
OH
H
Nandrolone 2.5 1
(injectable)
H O
O
40
CH
3
CH
3
OH
CH
3
Oxymetholone 2.5 1
(oral)
H
CH
3
CH
3
OH
O

H N
N
Structure Activity Relationships in Androgens
CH
3
Anabolic Androgenic
CH
3
OH
CH
3
Stanozolol 3 1
(oral)
H
41
H
3
C
O
CH
3
CH
3
OH
CH
3
Dromostanolone 4 1
(oral)
H
CH
3
CH
3
OH
O

• 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. 5 a
-Reductase inhibitors:
– They prevent conversion of testosterone into dihydrotestosterone.
– Used for treatment of Benign Prostatic Hyperplasia (BPH).

43
Androgens Antagonists
CH
3
OH
CH
CH
3
N
O
Danazol
(endometriosis)
CH
3
CH
3
O
N
H
CH
3
CH
3
CH
3
O N
H H
Finesteride ( 5 a reductase inhibitors)
(baldness)
Cyproterone acetate
(prostate cancer)
H N
O
CH
3
CH
3
CF
3
NO
2
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 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

Diet
Liver
25-OHase
OH
OHase = hydroxylase
HO
Vitamin D
UV from sunlight
Skin
3
HO
25(OH) D
3
Kidney
1-OHase
Specific receptors in intestine, bone, kidney
OH
Ca:
Intestinal absorption
Renal reabsorption
HO
7
Provitamin D
3
(7-dehydrocholesterol:
Intermediate in cholesterol synthesis)
HO
OH
1,25(OH)
2
D
3
(active hormone form)
Photobiosynthesis of vitamin D
3 and its metabolism
PO
4
:
Intestinal absorption
Renal reabsorption

The hormonal interactions controlling bone mineral homeostasis

Intestine
Actions of Vitamin D on Gut, Bone, and Kidney
Vitamin D
Increased calcium and phosphate absorption by 1,25
(OH)
2
D
Kidney
Bone
Calcium and phosphate excretion may be decreased by
25(OH)D and 1,25(OH)
2
D 1
Increased calcium and phosphate resorption by
1,25(OH)
2
D; bone formation may be increased by
1,25(OH)
2
D and 24,25(OH)
2
D
Net effect on serum levels
Serum calcium and phosphate both increased