Steroidal hormones

Hormones are agents secreted by endocrine glands (ductless)

and transported by the blood to exert their characteristic
effects upon certain specific tissues other than tissues or
glands of origin.

Phenancerene Perhydrophenancerene Cyclopentane

12 17
13
11
C D 16
1
10 9 14
2 8 15
A B
3 7
5
4 6
Cyclopentanoperhydrophenancerene
 and  Configuration
-Configuration.
-Configuration.
OH
CH3 CH3 CH3

A B A B D

HO HO

3-Hydroxy 3-Hydroxy 17-Hydroxy-17-methyl

CH3

CH3 C O

A B
D
O

C=O at C3 not  or  Methyl group attached to C=O

not designated by  or .
Stereochemistry
4 C
3 C
B
2 A 5 2 1 B
A
1 3 4 5

5Series ……………….. rings A &B are trans).

5Series ……………….. rings A &B are cis).

Rings B and C are always trans in nature.

Rings C and D are trans in all steroids except;

cardiac glycosides and toad poisons.
Nomenclature and numbering
20
18 R3
12 R2
17
11 16
19 13
1 R1
10 15
2 9 14
8

3
5 7
4 6
 Name R1 (-C10) R2 (-C13) R3 (-C17) No. of carbon
atoms
1) Gonane H H H 17
(perhydrocyclopentyl
phenantherene)

2) Estrane H CH3 (18) H 18

3) Androstane CH3 (19) CH3 (18) H 19

(20) (21)
4) Pregnane CH3 (19) CH3 (18) CH2CH3 21

(20) (22) (23)(24)

5) Cholane CH3 (19) CH3 (18) CH CH2CH2CH3 24

CH3
(21)

(20) (22)(23)(24)
6) Cholestane CH3 (19) CH3 (18) CH CH2CH2CH2 27

CH3 (25) CH CH3(26)

(21)
CH3
(27)
Prefix and suffix on nucleus
Function group Prefix Suffix
OH Hydroxy Ol
C=O Oxo One
COOH Carboxy Oic
-O- Epoxy Ether
NH2 Amino Amine
CHO Formyl Al
Cl, Br &I Halo -
C=C (not used) Ene
C C (not used) Yne
Prefix Hydrocarbon Suffix I II III IV V

C=C C C COOH C=O OH NH2 -O-

Examples of nomenclature 21
21 CH2OH
CH2OH
20 20
18 C O 18 C O
12 CH3 12 CH3 17
17 OH
HO 11
11 16
19 13 19 16
CH3 13
1 1 CH3
10 15
2 9 14 10 15
8 2 9 14
8
3
5 7 3
O
4 6 5 7
O
4 6
11, 17Trihydroxypregn-4-ene-
21-Hydroxypregn-4-ene-
3,20-dione.
3,20-dione.
Biosynthesis of some natural sexCHhormones 3 CH3
C O C O
OH
Oxidation Hydroxylation

HO HO HO
Cholesterol Pregnenolone 17-HydroxyPregnenolone
CH3 (1) Oxidation
(1) Desmolase enz.
C O CH3 Oxidation (2) Oxidation
(2) Isomerisation O
C O
OH

O Hydroxylase enz.
Progesterone
HO
O Prasterone
17-hydroxyProgesterone
(1) Desmolase enz. Reduction OH
O (2) Oxidation (1) Oxidation
OH (2) Isomerisation enz. 1) Reduction
enz.
2) Isomerase
enz.
(1) Oxidation
Reductase enz.
(2) isomerase HO 3) Aromatase
O O Androstenodiol
Androstenedione Testosterone enz.
Aromatisation
OH Aromatase enzyme
Reductase enz. O OH
OH Reductase enz.

Reduction
Reduction
Oxidation
Hydroxylase enz.
HO
Estriol HO HO
Estrone Estradiol
Biosynthesis of aldosterone and cortisol
CH3 CH3
C O C O
OH

Hydroxylase enzyme

O O
Progesterone 17-hydroxyProgesterone
Hydroxylase enz.
Oxidation Hydroxylase enzyme

CH2OH CH2OH
C O C O
OHC
HO HO OH

O O
Aldosterone Cortisol

CH2OH
OH
C O
O CH

O
Hemiacetal form of aldosterone
 Steroidal hormones
(A) Sex hormones
They are produced by genital glands and they are classified
into three groups, estrogens, progestins and androgens
(B) Adrenocortical hormones
1) Mineralocorticoids.
2) Glucocorticoids.

SEX HORMONES
These hormones play profound roles in reproduction, in the
menstrual cycle, and in giving women and men their
characteristic physical differences.

In The female
Two gonadotropic hormones are involved (that is, follicle
stimulating hormones (FSH) and luteinizing hormone (LH).
 A) Estrogens
Estrogens are female sex hormones.
In the female, they are produced by the ovary, placenta, and
adrenal cortex.

In the male, they are produced by the testes and the adrenal
cortex.

The major natural human estrogens are estradiol, estrone,

and estriol.

Esradiol is secreted by the ovary.

In vivo it is readily dehydrogenated to estrone, the major
estrogen present in the blood.

Estrone is metabolized to estriol, the most abundant

estrogen eliminated in the urine.
Clinical uses of estrogens
1- As contraceptives in combination with progestins.
2- Treatment of ovarian failure
3- Dysmenorrhea.
4- Menopausal symptoms for the relief of symptoms such as:
hot flashes, headache, dizziness and emotional instability.
5- Cancer of the prostate gland and postmenopausal breast
cancer.
6- Hirsutism (excessive face and body hair) in women.

CH3
Notes on the structure of estrogens
a- The parent hydrocarbon skeleton is estran (C18).
b- Ring A is benzenoid.
c- Absence of the CH3 group at C10 (C19).
d- They lack a carbon side chain at C17. HO
e- They all have a phenolic OH group at C3.
Types of estrogens: -
(I) Natural estrogens (estradiol, estrone and estriol).
(II) Semisynthetic estrogens (ethinylestradiol and mestranol).
(III) Synthetic non-steroidal estrogens.

1- Natural estrogens
Estradiol is the most potent and the major secretory
product of the human ovary. It is readily oxidized in
the liver to estrone, which in turn can be hydrated to
estriol.
 (1) Estradiol
(IM, implantation pellets)
It is natural estrogenic form. It has been isolated from
ovarian follicular fluid and from placental tissue, and is
the most active form of the natural steroid estrogens.
OH
CH3

HO
Estra-1,3,5(10)-triene-3,17-diol.
Or
3,17-Dihydroxyestra-1,3,5(10)-triene.
Synthesis
It is synthesized from the naturally secreted estrone, which is
abundant in the urine of pregnant mares.
O OH
CH3 CH3

LiAlH4
reduction

HO HO
Estrone Estradiol

*** Estradiol is inactive when taken orally.

*** It has a very short duration of action less than 1 hour

when taken IM or IV.
Depot preparations of estradiol
** It is obtained by esterification of hydroxyl groups by long
chain fatty acids.
*** With increasing the fatty acid chain length enhancement
of the lipid solubility was observed with decreasing the
rate of absorption and prolonged duration or depot action
was obtained.

*** These preparations are not given orally (it is inactive) but
given IM in an oily solution.
OR2
CH3

R1O
 Ester R1 (at C3) R2 (at C17) Duration of Relative
action potency
O
1) Estradiol benzoate C H 3 days 1/3

2) Estradiol valerate H CO-(CH2)3-CH3 3 weeks

(Estradiol pentanoate)

3) Estradiol dipropionate CH3-CH2-CO- CH3-CH2-CO- > 3 weeks

4) Estradiol cyclopentyl- H H2C H2C 3-8 weeks

propionate CO

*** The one ampoule may contain one ester or more than one ester.
*** These esters consider as prodrugs. They are inactive outside but
active in vivo after enzymatic hydrolysis in the biological system
(by esterase enzymes).
Natural metabolites of estradiol (Biotransformation)
O OH OH
CH3 CH3 CH3

OH
[H] Hydroxylase enz.
[O]

HO HO HO
Estrone Estradiol Estriol

Estriol = 1/60 of the activity of estradiol.

Estrone = 1/3 of the activity of estradiol.
** Another metabolites were found due to conjugation with
glucuronic acid or with sulphate. These metabolites
excreted in the urine.

Assay of estradiol
1- Colourimetrically (by Kober method).

2- Spectrophotometrically at  max 231 nm.

3- By biological method.
 (2) Estrone
(IM, vaginal and topical)
O
CH3

HO
3-Hydroxyestra-1,3,5(10)-trien-17-one.
It is only one third (1/3) as active as estradiol.

It was originally obtained from the urine of pregnant mares

(about 10 mg/L).
Synthesis
From Cholesterol
O
1- Acetylation
2- Hydrobromination (HBr)
3- Oxidation

4- Dehydrobromination
HO HO
(alc. KOH)
Cholesterol 5- Deacetylation
Catalytic hydrogenation

OH OH

Br Br2 / glacial acetic acid

Bromination
HO HO
Br
Dehydrobromination
(Alc. KOH), heat
O O
OH

Oxidation Pyrolysis

350o
O HO
HO Estrone
Assay
1- Spectrophotometrically by UV light, using the maximum
absorption at 280 nm (in EtOH).
2- By radio immune assay for assay of estrone in plasma.

3- Estriol
(Orally active)
OH
CH3

OH

HO

Estra-1,3,5(10)-triene-3,16,17-triol.
*** It is isolated from the urine of pregnant women.
*** The activity of estriol =1/60 of the activity of estradiol.
Metabolism of estrogens
*** Estrogens conjugate primarily in the liver with
glucouronic
or sulphuric acids

*** Two conjugates have been isolated from natural sources

estriol glucuronide
OH andCOOH
estrone sulphate.
CH3
O

O HO

OH HO3SO

OH
Estriol glucuronide Estrone sulphate

The conjugation renders this estrogen to be water-soluble

and facilitates its transport.