PROGETINS

INTRODUCTION
• These are substances which convert estrogen primed
endometrium to secretory and maintain pregnancy
• In addition to estrogens, progestin's are important
female sex hormones. Progesterone is main
hormone produced in the ovaries, testes and the
adrenal glands.
• Progestin’s are hormones which favors
pregnancy

NATURAL PROGESTIN
PROGESTERONE (21 CARBON STEROID) is derived from
cholesterol
It was first isolated in 1929
It is secreted by corpusluteum (10-20mg/day) in later half of
menstrual cycle under influence of LH. If ovum gets fertilized
and implants-the blastocyst immediately starts producing
chorionic gonadotropin which is absorbed and sustains the
corpus luteum in early pregnancy. Secretion of progesterone
starts from placenta from 2nd trimester till term
Males also produce 1-5mg progesterone per day from adrenals
and testes
[BUT ROLE IN MALES IS NOT KNOWN]

Synthetic progestin's
Progesterone
derivatives-
These are pure progestins
They have weaker anti-
ouvlatory action and are
used primarily as adjutants
to estrogens for
HRT, threatened
abortions, endometriosis
19-
nortestosterone
derivatives-
they have weak
estrogenic androgenic
and anabolic action but
have potent anti
ovulatory action.they
are mainly used in
combined contraceptive
pills.
Like Desogestrel and
Norgestimate (prodrug)

1
PROGESTERONE
DERIVATIVES
Medroxyprogeste
rone acetate
Megestrol
acetate
Dydrogestrone
Hydroxyprogeste
rone caproate
2
19-
NORTESTOSTERONE
DERIVATIVES (OLD)
Norethindrone
Lynestrenol
Allylestrenol
Levonorgestrel
(gonane)
3
19-
NORTESTOSTERONE
DERIVATIVES (NEW)
Desogestrel
Norgestimate
Gestodene

ACTIONS
It prepares uterus for nidation and helps in maintance of
pregnancy by preventing endometrial shedding, decreases
uterine motility and inhibiting immunological rejection of fetus
( T cell function and cell mediated immunity)
Specific actions
• Uterus- secretory changes in estrogen primed endometrium
(hyperemia, tortuocity of glands and increased secretion).
Continued action of progesterone cause decidual changes in
endometrium (stroma enlarges, becomes spongy, glands
atrophy and decreases sensitivity of myometrium to oxytocin)
• Cervix-converts watery secretion (estrogen produced) to
viscid, scanty and cellular which is hostile to sperm penetration
• Vagina- induces pregnancy like changes in the mucosa-
leukocyte infiltration of cornified epithelium

Continued…
• Breast - it causes proliferation of acini in the mammary
gland. Acting along with estrogen which prepares the breast
for lactation
• CNS - may have sedative effect
• Body temperature -causes slight (0.5 C) rise in body
temperature.
• Respiration -may stimulate respiration at high doses
• Metabolism -prolonged use of OCP impairs glucose
tolerance. They also tend to raise LDL and lower HDL(ie.19-
nortestoserone derivatives)
• Pitutary -progesterone is a weak inhibitor of Gonadotrophin
secretion

Mechanism of action
The progesterone receptors (PR) has limited
distribution in the body confined mainly to the
female genital tract, breast, CNS and pitutary.
Upon hormone binding PR undergoes
dimerization, attaches to progesterone response
element (PRE) of target genes and regulate
transcription through coactivators.

AR = Androgen receptor; ER = Estrogen receptor;
GR = Glucocorticoid receptor; MR = Mineralocorticoid receptor;
PR = Progesterone receptor.

Pharmacokinetics
 Progesterone is orally inactive because of high first pass
metabolism in liver. Hence mostly given by i.m in oily
solution. I.m doses are rapidly cleared from plasma with a
short t1/2 (5-7 mins) and nearly completely degraded in liver
(major product pregnananediol excreted in urine as
glucuronide and sulphate conjugates). However the effects
of progesterone lasts longer
 Micronized formulation has been developed for oral
administration which contains micro fine particles of
progesterone suspended in oil and dispensed in gelatin
capsules. Its absorption occurs through lymphatics
 Most synthetic progestins are orally active, metabolized
slowly, and have plasma t1/2 btw 8-24hrs

Adverse effects
 Breast engorgement, head ache, rise in body
temp, edema, esophageal reflex, acne and mood swings
may occur with higher doses
 Irregular bleeding (amenorrhoea) may occur if given
continuously
 19-nortestosterone derivatives lower plasma HDL level there
by may promote atherogenesis ( not seen in progesterone
and its derivatives)
 Long term use in HRT may increase risk of breast cancer
 Blood sugar may rise and diabetes may be percipitated by
long term use (levonorgestrel)
 Intramuscular injections of progesterone are painful
 If given in early pergnancy they can cause masculinization of
female foetus or other congenital abnormalities

Uses
I. As contraceptive- postcoital contraceptive (mifepristone-
600mg within 72hrs), once a month contraceptive
(mifepristone- 200mg 2 days after mid cycle)
II. Hormone replacement therapy (HRT)-used in non-
hysterectomised post menopausal women estrogen therapy is
supplemented with a progestin for 10-12 days each month to
reduce the risk of endometrial carcinoma
III. DUB ( dysfunctional uterine bleeding)- progestin in large dose
(norethindrone 20-40mg/day) promptly stops the bleeding and
keeps it abeyance as long as thearpy is given . Cyclic treatment
regularizes and normalizes menstrual flow.
IV. Threatened habitual abortion- a pure progestin without
estrogenic or androgenic activity may show efficacy in
preventing premature delivery in high risk pregnancy

V. Endometriosis- mainly manifests as dysmenorrhea, painful
pelvic swellings and infertility. Progestin's induce anovulatory
hypoestogenic state by suppressing Gn release . Direct action
on endometrium prevents bleeding from the ectopic sites by
suppressing menstruation. Treatment is usually given for a
few months which causes atrophy and regression of the
ectopic mass and the therapy is usually withdrawn within 6
mths
VI. Premenstrual syndrome- manifested as
headache,irritability,fluid retention, distension and breast
tenderness a few days preceding menstruation . Fluoxetine
and other SSRIs (selective serotonin reuptake inhibitors) can
be given symptomatically. if sever PMS then suppression of
ovulation by combined estrogen progesterone treatment
given cyclically
VII. Endometrial carcinoma – progestin's are palliative in about
50 % cases of advanced or metastatic endometrial carcinoma

Preparations and Dose
1. Progesterone : 10-100 mg i.m OD;
PROGEST, PROLUTON, GESTONE, NATUROGEST, OGEST.
2. Hydroxyprogestrone caproate : 250-500 mg i.m at 2-14 Days
intervals; PROLUTON DEPOT, MAINTANE INJ, PROCAPRIN.
3. Medroxyprogesterone Acetate : 5-20 mg OD-BD oral, 50-150
mg i.m at 1-3 months interval;
FARLUTAL, PROVERA, MEPRATE, MODUS, DEPOT-PROVERA.
4. Dydrogesterone : 5-10 mg OD/TDS oral; DUPHASTON.
5. Norethindrone : 5-10 mg OD-BD oral; PRIMOLUT-
N, STYPTIN, REGESTRONE, NORGEST, REGESTRONE
HRT, NORETA HRT, NORISTERAT.
6. Lynestrenol (Ethinylestrenol) : 5-10 mg OD oral; ORGAMETRIL.
7. Allylestrenol : 10-40 mg/day;
GESTANIN, FETUGARD, MAINTANE, PROFAR.
8. Levonorgestrel : 0.1-0.5 mg/day; DUOLUTON-L, OVRAL.
9. Desogestrel: 150 micro g + Ethinylestrenol 30 micro g
NOVELON 1 Tab OD 3 week on 1 week off cyclic therapy.

BIRTH CONTROL PILLS (PROGESTIN ONLY)

Progestin-only hormone implant (Implanon)
The progestin-only hormone implant releases hormones
that prevent pregnancy for 3 years. It must be inserted and
removed by a trained health professional. The actual
implant is about the size of a matchstick and is inserted
under the skin on the inside of the upper arm

ANTIPROGESTIN
Progestational antagonists
What would happen if during pregnancy we introduce a
progesterone antagonist?
The antagonist will bind the receptor with high affinity.
It will exclude progesterone from the binding site and
hence eliminate its agonist activity.
Thus pregnancy which is dependent on the progesterone
activity will no longer be able to sustain. The fetus will
hence be aborted.
This is the function of Mifepristone
Mifepristone is a progesterone antagonist.

Mifepristone
It is a 19-nonsteroid with potent competitive anti-
progestational, anti-glucocorticoid and anti-androgenic activity.
Mifeprestone is a partial agonist and competitive antagonist of
both A and B forms of PR. In absence of progesterone it exerts
weak progestational activity.

Mifepristone is administered during:
Follicular phase : its anti progestin action causes attenuation
of mid-cycle gonadotrophin surge from pituitary there by
slowing follicular development and delay or failure of ovulation.
Luteal phase : it prevents secretory changes caused by
progesterone .
Later in the cycle : blocks progesterone support to the
endometrium , unrestraint PG release from it there by
stimulating uterine contraction. It also sensitizes myometrium to
PG’s inducing menstruation.
Implantation phase : blocks decidualization causing the
dislodgement of conceptus , fall in HCG production and
secondary luteolysis .

Pharmacokinetics
 Mifeprestone is orally active with a bioavailability of
25 %.
 Mainly metabolized in the liver and excreted in bile .
 It has a t ½ of 20-36hrs .
 It interacts with CYP3A4 inhibitors (
erythromycin, ketoconazole ) and inducer of
(rifampin and anti-convulsants)

Uses
1. Termination of pregnancy : upto seven weeks- 600mg oral causes
complete abortion in 60-85% cases . To improve success rate a
single 400mg oral dose of misoprostol can be given 48hrs later. In
place of misoprostol 1mg gemeprostpessary can be inserted intra-
vaginally.
{side effects :prolonged bleeding ,failed
abortion, anorexia, nausea, tiredness, abdominal
discomfort, uterine cramps etc }
2. Cervical ripening: 600mg administered 24-30 hrs before
attempting surgical abortion or induction of labour
3. Post-coital contraceptive : 600mg within 72 hrs of intercourse
prevents implantation
4. Once a month contraceptive: 200mg administered 2days after
mid cycle each month prevents conception
5. Induction of labour : action by blocking the relaxant effect of
progestrone on uterus of late pregnancy it induces labour in cases
of intra uterine fetal death and abnormal fetus
6. Cushing’s syndrome : pallative effect due to its glucocorticoid
receptor blocking property

MTP Kit COMPOSITION
Each pack contains 5 tablets -
1 tablet of Mifepristone…200 mg
4 tablets of Misoprostol, each containing
Misoprostol…200 mcg

PROGETINS

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PROGETINS