Progestins (Progestagens)
*** Progestins are female sex hormones.
*** The natural ones are secreted mainly by the corpus luteum
and placenta.
*** The most abundant natural progestin is progesterone.
***It is not active when taken orally, but synthetic progestins
are active in oral doses.
Medicinal uses
1- As contraceptives in combination with estrogens.
2- Excessive uterine bleeding.
3- Dysmenorrhea.
Progesterone
(IM, vaginal gel) CH3
C O
CH3
CH3
O
Pregn-4-ene-3,20-dione.
** It is not effective orally, it is given parenterally, with very
short duration (about 5 minutes).
*** It is used in combination with estrogens in contraceptives
pills.
Assay
Spectrophotometrically at max 241 nm (in absolute ethanol).
A) Progestins derived from progesterone
(17-Hydroxyprogesterone derivatives)
CH3 CH3
C O C O
CH3 CH3
OH
CH3 CH3
Hydroxylation
O O
Progesterone 17-hydroxyprogesterone
(i) Esterification of 17-OH group.
(ii) Introduction of a substituent at C6.
CH3
C O
CH3
OCOR
CH3
R'
Compound R' R Administration
route
1- Hydroxyprogesterone hexanoate H (CH2)4CH3 IM
(Hydroxyprogesterone caproate)
2- Medroxyprogesterone acetate -CH3 CH3 Orally
(Provera)
1- Hydroxyprogesterone hexanoate
(Hydroxyprogesterone caproate)
CH3
C O O
CH3
O C (CH2)4CH3
CH3
O
17-Hydroxypregn-4-ene-3,20-dione hexanoate.
*** It is much more active and longer acting than progesterone,
because the 17ester function hinders the reduction of
the 20-One, to the 20-Ol.
*** It is given only IM.
*** The hexanoate ester greatly increases the oil solubility,
decreases the rate of absorption and allowing it to be slowly
released. Finally prolonged duration or depot action
2- Medroxyprogesterone acetate
(Provera) CH3
C O O
CH3
O C CH3
CH3
CH3
17-Hydroxy-6-methylpregn-4-ene-3,20-dione acetate.
Or 17-acetyloxy-6-methylpregn-4-ene-3,20-dione.
*** It contains 6-methyl group adds to the 17-
hydroxyprogesterone
structure, this will greatly decrease the rate of reduction of the 4-
en-3-one system.
*** The 17-acetate group also decreases reduction of the 20-one, just
as with 17-caproate.
*** Medroxyprogesterone acetate is very active orally, and
has much a long duration of action intramuscularly.
Uses
In oral contraceptives, treatment of menstrual disorders, endom
etrial carcinoma in addition to other uses for progestins.
Assay
Specrtophotometrically at max 241 nm.
Structure activity relationship of this group:
1- All these compounds are strongly active progesterone more
potent than progesterone itself.
2- Esterification of the OH group in C17 increase the lipid
solubility and decrease the absorption from the site of
injection so, it gives depot action. Also this ester moiety at
C17 protects the (C=O) adjacent from being reduced by
reductases through its steric effect (reduction in biological
system is the reason of deactivation).
3- Substitution at the position 6 with methyl or chloro group
will protect the 6 position and adjacent vulnerable sites
from being biotransformed and biooxidized and thus
rendering these compounds more potent, longer duration
and orally active.
(B) Progestins derived from testosterone and
nortestosterone (17-Ethinyltestosterone)
In these compounds the acetyl group at C17 in progesterone
is completely substituted by 17-hydroxy and 17-ethinyl
groups.
1- Ethisterone (oral)
OH
CH3
C CH
CH3
17-Ethinyl-17-Hydroxyandrost-4-en-3-one.
It is progestational compound, it is highly orally active, and it
is used in oral contraceptives.
2- Norethindrone (Norethisterone)
(oral)
OH
CH3
C CH
17-Ethinyl-17-Hydroxy-19-norandrost-4-en-3-one.
General characters of this group
1- They are more potent than natural hormone.
2- Orally active.
3- They are not biotransformed to corticosteroids.
4- They suffer from some side effects such as;
a- They have some androgenic properties as side effects, due
to structural similarity to testosterone.
b- They have structural similarity to estrogens, therefore,
they have estrogenic properties, due to the absence of
CH3 group at carbon no.10, These estrogenic properties
will inhibit ovulation by –ve feed back mechanism process
by inhibition of LH and FSH (estrogenic side effects).
So these compounds are mainly progestional ones with some
estrogenic and androgenic properties as side effects.
Uses
They are involved in small doses in oral contraceptive pills as
progestional components.
Structure activity relationship
1- Presence of 4-en-3-one in ring (A) is essential for maximum
activity, shifting of the double bond to 5(10) position gives a
compound, which retains only 1/10 activity (norethynodrel).
2- 19-Nor derivatives (without methyl group ( no. 19) are more
strong as progestational agents, the absence of CH3 group
no. 19 helps the fitting of the compound to its receptors,
therefore gives much potent progestational activity. So,
norethisterone is more active than ethisterone.
3- The ethinyl group at C17 yields an orally active drug and
prevents oxidation of C-17 OH into C17 (C=O) and protect
C16-17 bond from attack by intestinal microflora.
4- Esterification at C17 will protect C=O at C20 and also protect
bond at C16-17 bond and prevent its cleavage.
Assay of progestational compounds
O2N NHNH2 O2N NH N
+
O
NO2 NO2
Highly coloured compound
Antiprogestins
CH3 Ru 486 (Mifepristone)
H3C N
OH
CH3
C C CH3
O
*** Ru 486 binds strongly with both the glucocorticoid
receptor and with the progesterone receptor.
*** When progesterone binds to its receptor, heat shock
protein is released from the receptor and thereby opens
the progesterone-receptor complex to DNA binding.
*** However, when RU 486 binds to the progesterone receptor,
heat shock protein is not released: therefore, no
transcription of the DNA can occur.
*** Alternatively, RU 486 may induce a conformational change
in the progesterone receptor so that it does not fit its DNA
site.
*** Ru 486 is used also in the treatment of progesterone
sensitive cancers and in Cushing’s syndrome
(overproduction of glucocorticoides).
