PROGESTINS
AND
ANTIPROGESTINS
1
Learning Objectives
At the end of the lecture , students
should be able to-
Enlist the available synthetic
Progestins
Describe the mechanism of action of
Progestin, pharmacological cations and its
side effects
Describe the mechanism of action and
clinical indications of AntiProgestins
NATURAL PROGESTERONE
Introduction
Progesterone (21 carbon steroid) is derived from
cholesterol
It was first isolated in 1929
Males also produce 1-5mg progesterone per day from
adrenals and testes [but role in males is not known]
Progestins
NATURAL PROGESTERONE
Converts the estrogen primed proliferative endometrium to secretory and maintain pregnancy in animals spayed after
conception
●
Progesterone
●
Secreted form corpus luteum post-ovulation and immediately after fertilization (corpus luteum sustained by
chorionic gonadotrophins released by blastocyst); from placenta during 2nd and 3rd trimester; from adrenals
Natural Progestin:
Progestin preparations
Progesterone Newer
analogues 19-Nortesterone 19-Nortesterone
derivatives derivatives
Hydroxy progesterone Norethisterone Desogestel*
Medroxy progesterone Norethynodrel Norgestimate*
Megesterol acetate Ethinylesterol Gestodene
Dihydrogesterone Norgestrel
Nomegestrol* Levonorgestrel* Potent & pure progestins
No androgenic
Strong Antiovulatory
Progestogenic , Anabolic activity
Pure progestins Weak androgenic & estrogenic
Weak androgenic & Potent Antiovulatory
Antiovulatory activity Don't antagonise the
Along with oestrogen beneficial effects of E.
HRT in P.M.W Contraceptives along
Threatened abortion with estrogens.
Contraceptive along
Endometriosis- for Lipid friendly.
with estrogens
selective p effect Rx of hyperandrogemia.
PHARMACODYNAMICS
PROGESTINS
Bind to nuclear receptors (PR-A and PR-B)
Dimerization & conformational
change in PR
Bind to PREs, recruiting co-
activators
transcription of target genes
Progesterone
• Progesterone Receptors:
– Limited distribution: female genital tract, breast, CNS, pituitary
– Nucleus of target cells
– Short (PR-A) and Long (PR-B) isoforms
• Mechanism of Action:
– Binds to Progesterone Receptor (PR) present in nucleus Undergoes
conformational changes (dimerization) attaches to Progesterone
Response elements (PRE) regulates transcription through coactivators
– Cell membrane receptors: rapid effects (Ca++ release from spermatozoa,
Oocyte maturation)
Progesterone: Pharmacokinetics
Pharmacokinetic Parameters Profile
Absorption • Inactive orally, high first pass metabolism in liver
• Injected intramuscularly as oily preparation
• Micronized formulation for oral administration; absorption
through lymphatics
Distribution • Short half life (5-7 mins)
Metabolism • Converted to Pregnanediol in liver
• Conjugation with glucuronic acid and sulfation
Excretion • Excreted in urine
• Effects lasts longer than the hormone itself
• Synthetic Progestins: orally active, metabolized slowly; longer half life
USES OF PROGESTINS
Life span of female
Contraception. HRT(adjuvant)
Menarche DUB Menopause Endometrial
Endometriosis carcinoma
Threatened
and habitual
abortion
Postponement
of periods
PROGESTINS
THERAPEUTIC USES
●
Contraception: alone or in combination with estrogen.
●
MHT
●
Ovarian suppression
●
Dysmenorrhea
●
Endometriosis
●
Dysfunctional uterine bleeding (DUB)
●
Threatened and habitual abortion
●
These agents are used in the treatment of endometrial carcinoma and endometrial hyperplasia.
●
Premenstrual syndrome.
●
These agents are used diagnostically to evaluate endometrial function in amenorrhea.
SIDE EFFECTS OF PROGESTINS
• Natural(micronized) progesterone
Fatigue
Somnolence
• Synthetic
progestins
Acne
Alopecia Anxiety
Hirsutism Depressio
Hoarse voice n Myalgia
Fluid retention Oedema
Abdominal bloating
Mifepristone
Blocks Blocks Antiandrogenic &
Decreases the
[Link] progesterone Antiglucorticoid
progesterone
support to secretion
endometrium
Contragestational
agent Softens
Endometrial the cervix
x
R Cushing
syndrome
shedding
PG release Favourable
Pregnancy for Abortion
termination
Uterine Sensitises the
contractions myometrium
to [Link]
Conceptus detached
from uterine wall Facilitates menstruation
Mifepristone Uses
1. Termination of pregnancy- up to 7wks.
Mifepristone(600mg,orally) + Misoprostol(400mg
orally) / Gemeprost (1mg as pessary).
Midterm abortion-(13-24wks)-Mifepristone +
Gemeprost.
If adm within 10days of missed period results heavy
period.
Its not effective after 7wks, becoz later placenta starts
enough P to over come the antiprogestin effects of
mifepristone.
[Link] contraceptive-
Mifepristone -within 72hrs of intercourse, interferes
with implantation.
Effective method for emergency contraception.
[Link] cervix-Mifepristone soften & dilates cervix,
prior to surgical abortion/ labour induction.
[Link] induction of labour- intrauterine foetal death.
[Link] fibroids.
[Link] dependent brain neoplasm.
[Link] cancer.
8. Cushing's syndrome- as a palliative.
S/E:- abortion failure, prolonged bleeding, abdominal
cramps, vomiting, diarrhoea & anorexia.
D.I- with [Link]/inhibitors are observed.
Onapristone- newer Antiprogestin & effective.
In which of the following condition progestin is used alone without
combining with an estrogen:
A. Threatened abortion
B. Dysfunctional uterine bleeding
C. Hormone replacement therapy
Mefipristone is a:
a)Aromatase inhibitors
b)Antiprogestin
c)SERM
A breast feeding women was taking oral contraceptives, after few months she noticed
some hair growing on her face and acne, which one of the following drugs would cause
her symptoms?
A. Norethindrone
B. Norgestimate
D. Desogestrel
Which of the following is synthetic Progesterone devoid from systemic androgenic
effect?
A. Norethindrone
B. Norgestrel
C. Medroxyprogesterone acetate
D. Norgestimate
Which of the following can act as a single dose postcoital contraceptive:
A. Clomiphene citrate
B. Ethyinyl estradiol
C. Norgestimate
D. Mifepristone
Mifepristone possesses the following activities:
A. Potent anti-progestin + weak androgenic
B. Potent anti-progestin + weak antiglucocorticoid
C. Potent anti-estrogenic + weak antiprogestin
D. Potent anti-estrogenic + weak glucocorticoid