PROGESTINS

Dr Suyash Bharat
MD Pharmacology
GMC haldwani
 Introduction
• Progestin  favouring pregnancy.
• Natural progestin – progesterone 21C steroid ,
derive from cholesterol , secreted by corpus
luteum* / placenta*
• Synthetic progestins – high oral activity
-progesterone derivatives (21C) – apart from
progesteronal activity it have weaker
antiovulatory axn
 Blastocyst secrete

WITHDRAWL OF
E & P coz release
of prolactin from
pitutary milk
secretion starts

Placenta secrete E & P from

2nd trimester
• 19-nortestosterone derivatives  Estranes(18 C)
- progesteronal activity, potent antiovulatory *
axn , weak estrogenic, androgenic, anabolic axn.
• Estranes with a 13–ethyl substitution  Gonanes
increase potency antiovulatory * axn & reduced
androgenic activity.
• * Suppress GnRH
 Physiological and Pharmacological
Actions
• Neuroendocrine Actions decreasing the
frequency of GnRH pulses.
• Reproductive Tract decreases estrogen-
driven endometrial proliferation  l/t
development of a secretory endometrium 
abrupt decline  onset of menstruation.
• Endocervical glands secretion turn to scant,
viscid material.
• Progesterone  imp for maintenance of
pregnancy suppresses menstruation and
uterine contractility
====
• Mammary Gland. Development requires both
estrogen & progesterone.
• During pregnancy acting with estrogen,
brings proliferation of the acini of the
mammary gland. Toward the end of
pregnancyacini fill with secretions &
vasculature of the gland increases
• After the levels of estrogen and progesterone
decrease at parturition does lactation begin.
• Under influence of progesterone mitotic
activity in the breast epithelium is very low in
the follicular phase and then peaks in the luteal
phase .
 CNS Effects.
• During a normal menstrual cycle, an increase in
basal body temperature of about 0.6°C (1°F) at
mid-cycle correlates with ovulation.
• Progesterone also increases the ventilatory
response of the respiratory centers to CO2 and
leads to reduced arterial and alveolar PCO2 in the
luteal phase of the menstrual cycle and during
pregnancy.
• Progesterone also may have depressant and
hypnotic actions in the CNS, possibly accounting
for reports of drowsiness after hormone
administration.
 Metabolic Effects
• Progesterone  increases basal insulin levels &
the rise in insulin after carbohydrate ingestion, but
it does not normally alter glucose tolerance.
• Long-term administration of more potent
progestins decrease glucose tolerance.
• Progesterone stimulates lipoprotein lipase
activity and seems to enhance fat deposition.
• Progesterone & analogs (MPA) increase LDL &
no/little reductions in sr HDL levels.
• 19-norprogestins (androgenic activity)
effects on plasma lipids
• Micronized progesterone does not
significantly affect beneficial estrogen effects
on either HDL or LDL profiles.
• Progesterone diminish effects of
aldosterone in the renal tubule and cause a
decrease in Na+ reabsorption  increase
mineralocorticoid secretion from the adrenal
cortex.
 Mechanism of Action
• Single gene encodes two isoforms of the
progesterone receptor (PR): PR-A and PR-B. The
first 164 N-terminal amino acids of PR-B are
missing from PR-A.
• The ratios of the individual isoforms vary in
reproductive tissues as a consequence of tissue
type, developmental status, and hormone levels.
• Both PR-A and PR-B have AF-1 and AF-2
transactivation domains, but the longer PR-B
also contains an additional AF-3 that contributes
to its cell- and promoter-specific activity.
• Ligand-binding domains  PR isoforms are
identical.
• In the absence of ligand, PR is present in the
nucleus in an inactive monomeric state bound
to heat-shock proteins (HSP-90, HSP-70, and
p59).
• Binding progesterone, HSPs dissociate 
receptors are phosphorylated  form dimers
(homo- and heterodimers) that bind with high
selectivity to PREs (progesterone response
elements) located on target genes
• Transcriptional activation by PR occurs primarily via
recruitment of co-activators such as SRC-1, NcoA-1, or NcoA-
2.
• The receptor-co-activator complex then favors further
interactions with additional proteins such as CBP and p300,
which have histone acetylase activity remodeling of
chromatin  increases the accessibility of general
transcriptional proteins, including RNA polymerase II, to the
target promoter.
• Progesterone antagonists also facilitate receptor
dimerization and DNA binding, but conformation of
antagonist-bound PR is different from that of agonist-bound
PR.
• This different conformation favors PR interaction with co-
repressors such as NcoR/SMRT, which recruit histone
deacetylasesincreases DNA interaction with nucleosomes
and renders a target promoter inaccessible to the general
transcription apparatus.
• In most cells, PR-B mediates the stimulatory
activities of progesterone; PR-A strongly inhibits
this action of PR-B and is also a transcriptional
inhibitor of other steroid receptors.
• PR-A antiproliferative effect
• PR-B mediating hormone effects in the
mammary gland .
• Progesterone increased Ca2+ mobilization in
sperm (membrane-bound progesterone
receptors).  spermatozoa and oocyte
maturation .
 Mechanism of Action
• PR nucleus of target cell(Female genital tract,
breast , CNS , Pituitary)

• P binding the PR undergoes DIAMERIZATION

• Attaches to Progesteron Response Element(PRE)

of target gene.

• Regulates transcription through co-activators

 Absorption, Fate, and Excretion
• Rapid first-pass metabolism
• IN PLASMA, bound by albumin and
corticosteroid-binding globulin.
• Elimination half-life 5 minutes eliminated in
the urine
• 19-nor steroids have good oral activity  ethinyl
substituent at C17  slows hepatic metabolism
• Synthetic progestins longer half-lives (7 -24 Hrs)
 Therapeutic Uses
• Contraception
• hormone therapy of postmenopausal women
• Secondary amenorrhea, abnormal uterine bleeding in patients
without underlying organic pathology (e.g., fibroids or
cancer),
• Luteal-phase support to treat infertility, and premature labor
• Progesterone can be used diagnostically to test for estrogen
secretion and for responsiveness of the endometrium.
• Highly efficacious in decreasing the occurrence of endometrial
hyperplasia and carcinoma caused by unopposed estrogens
• Hormone releasing IUD decrease estrogen-induced
endometrial hyperplasia
• Palliative measure for metastatic endometrial carcinoma
• Megestrol acetate 2nd-line treatment for breast cancer.
 ANTI-PROGESTINS AND
PROGESTERONE-RECEPTOR
MODULATORS
• Mifepristone- derivative of the 19-
norprogestin norethindrone progesterone-
receptor modulator (PRM)
• Competes with both progesterone &
glucocorticoids for binding to their respective
receptors.
• Onapristone, asoprisnil
• Pharmacological Actions. Mifepristone 
competitive receptor antagonist for both
progesterone receptors BUT exhibits some
agonist activity .
• Early stages of pregnancy, mifepristone causes
decidual breakdown (blockade of PR)
detachment of the blastocyst decreases hCG
productionThis coz decrease in progesterone
secretion from the corpus luteum accentuates
decidual breakdown.

• Sensitizes myometrium contractile actions.

Mifepristone cervical softening

• facilitates Expulsion of Blastocyst.

• Delay or prevent ovulation
• If administered for one or several days in the
mid- to late luteal phase, mifepristone impairs
the development of a secretory endometrium
and produces menses.
 Absorption, Fate, and Excretion
• Mifepristone  orally active with good
bioavailability.
• plasma t1/2 of 20 - 40 hrsbound by a1-acid
glycoprotein.
• Metabolites mono- and di-demethylated
products formed via CYP3A4-catalyzed
reactions.
• Drug  hepatic metabolism and enterohepatic
circulation
 Therapeutic Uses
• Mifepristone 600 mg  f/b 48 Hr later
Misoprostol (PGE1) 400mg Termination of
early pregnancy
Success rate  >90% among women with
pregnancies of 49 days.
• Cervical ripening-
• Postcoital contraceptives
• Adverse effect Vaginal bleeding (lasts from 8
to 17 days ) , abdominal pain and uterine
cramps, nausea, vomiting, and diarrhea

• CI Women receiving chronic glucocorticoid

therapy (anti-glucocorticoid activity)
Patient anemic or receiving anticoagulants.
Women with cardiovascular risk factors
 Ulipristal(selective progesterone
receptor modulator)
• Use- Emergency contraceptive

Inhibit ovulation (suppress LH surge)

Interfere with implantation
Thank you