Narayanan R ObGyan 2015. Progesterone Progesterone is also known as P4 (pregn-4-ene-3,20-dione) It...
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Transcript of Narayanan R ObGyan 2015. Progesterone Progesterone is also known as P4 (pregn-4-ene-3,20-dione) It...
PROGESTERONE
Narayanan RObGyan 2015
Progesterone
Progesterone is also known as P4 (pregn-4-ene-3,20-dione)
It is a C-21 steroid hormone involved in the menstrual cycle, pregnancy and embryogenesis
Progesterone is a compound with 21 carbon atom chain derived from cholesterol.It consists of four interconnected cyclic hydrocarbons, ketone and oxygenated functional groups, as well as two methyl branches.
Source of Progesterone Produced by the corpus luteum, adrenals and
placenta. It is also stored in adipose tissue . During early pregnancy, hCG from conceptus
‘rescues’ corpus luteum. Progesterone secretion continues from CL. After the 8th week, production of progesterone
shifts to the placenta. Consumption of milk products raises the level of
bioavailable progesterone. Progesterone-like steroid called diosgenin is found
in Mexican yam from which Progesterone can be produced.
Synthetic progesterone is called progestogens / progestins / gestagens.
Progesterone levels are low during the preovulatory phase It rises after ovulation, and is elevated during the luteal phase
Progesterone levels are < 2 ng/ml prior to ovulation and> 5 ng/ml after ovulation.
After the luteal-placental shift, progesterone levels may reach 100-200 ng/ml at term.
Pharmacokinetics:
In liver Reduction
hydroxylation
Conjugation
Glucuronide
derivatives
Excreted in urine &
feces
Used for detection of ovulation(urinary
metabolite)
Extensive first pass metabolism in liver & gut
¼ th reaches circulati
on
T1/2 -30 minReaches base line in 12
hrs
Peak levels in 2 hrs So requires BD dosage
Progestins
Advantages Disadvantages
Bypasses first pass metabolism,rapid hepatic inactivation
Androgenic ill effects
Good oral absorption Fluid retention
Good hemostats Decreases HDL
Good contraceptives PMS like symptoms
Not able to convey many of the biological benefits of native progesterone
Classification
Progestins
Synthetic
Structarally related to progesterone
Structurally related to testosterone
Natural
Progesterone
Related to progesteron
e
Pregnane derivatives
Acetylated MPAMegesterol acetateCyproterone acetateChlormadinoneacetat
e(minipill)
NonacetylatedDydrogesterone (duphaston)
19-norprogeste
rone derivatives
DemegestoneNomegesterolNestrone
drosperinone
Acetylated MPAMegesterol acetateCyproterone acetateChlormadinoneacetat
e(minipill)
NonacetylatedDydrogesterone (duphaston)
Related to testosterone
Ethinylated
Norethindrone lynestrenol
Norethinsterone (primolut-N)
NORETHINSTERONE ACETATE
(REGESTERONE)
GonanesLNG (OVRAL)DesogestrelGestodone
norgestimate
Nonethinylated
Dienogest
Pregnane derivative
Medroxy progesterone acetate (MPA)
Similar action as natural compound with lesser endometrial-stromal asynchrony.
Non androgenic Ideal for endometrial protection. Due to prolonged axis suppression it
is not ideal for withdrawal bleeding.
Didrogesterone
Induces production of progesterone-induced blocking factor ( PIBF ) thereby decreasing harmful Th 1 cells and increasing Th 2 cells which increases clinical pregnancy rates.
Advantages : Being diuretic it prevents sodium retention. No adverse effect on B.P. , weight, blood
clotting factors and lipoproteins. Adrenal and renal function are unaffected.
Estrane (I Generation): norehisterone, norethynindiol
Gonane (II Generation): levonorgestrel, norgestrel
Their strong inhibitory action on pituitary gonadotrophins and hemostatic activity make them effective contraceptives.
III Generation : Desogestrel, gestodene, norgestimate
They are lipid friendly & potent antiovulatory.
IV Generation: Drospirenone, dienogest, nomegestrol
Increased risk of thrombosis
Micronised progesterone:
Natural progesterone (decreased particle size increases absorption & bioavailability)
Serum progesterone is dose-dependent To protect endometrium- 300mg/day in
divided doses (100 mg day & 200mg night because sedation is the side effect) is required
Maximum absorption after food Short acting and needs multiple doses Lipid friendly Favours diuresis (so useful in HRT as
cardioprotective) Suitable for treatment of LPD, AUB, HRT, PMS
and progesterone challenge test
Clinical Applications
Oral progesterone is not water-soluble & is poorly absorbed with poor bioavailability
Capsules containing micronised progesterone in oil have improved bioavailability
Other routes: vaginal, rectal or transdermal
Gel, cream or injection
Side effects
Sodium / Fluid retention (Renin-Aldosterone system triggered by aldosterone receptors)
Androgenic SE ( if testosteron-derived)
PMS / Mood swings (stimulation of CNS progesterone receptors)
Drowsiness Erratic / Breakthrough bleeding
In Diagnosis:
Progesterone challenge test in secondary amenorrhea.
Androgen-derived progestins are more effective
Prior to ovulation induction, natural progesterone is preferred because of HPO axis suppression.
Contraception:
Progesterone contributes by: Inhibiting ovulation by inhibiting LH
surge Making cervical mucus thick Making endometrium non receptive
for implantation.
1960sEE 50mcg+NEa 4mg
1960sNorgestrel
Levonogestrel
1970sTriphasic Pill
1970sMicropill
EE30mcg+LevoNg150
1990s
2000EE 30/20 Drospirenone
1970sMinipill - POP
LevoNG 30mcg
2009Estradiol valerate+
Dienogest
E40%+LevoNG
Progestin in COC
Monophasic: Fixed Progestin dose Biphasic: Increased Progestin in second half
of cycle Triphasic: Increased Progestin in all 3 phases Progestin only Pill (POP): Suitable during
lactation
Extended Regimens:
Contraception for Emergency
LNG 1.5 mg single dose within 72 hours
LNG 0.75 mg within 72 hours of coitus &
2nd dose 12 hours later
Vaginal Ring
Made of copolymer 15 mg EE + 120
mcg Etonogestrel Active for 3 weeks Inserted &
removed by user Headache /
Leukorrhoea / vaginitis
Failure: 0.65/100wy
Induction of long-term ovarian suppression:
Dysmenorrhea Endometriosis (decidualization
followed by atrophy of ectopic endometrium)
Hirsuitism Bleeding disorders (where estrogens
are contraindicated) Precocious puberty Premenstrual syndrome
LNG releasing IUCD
LNG-20 (Mirena-Emily) Releases 20 mcg
LNG/Day Collar in vertical arm
has 52 mg LNG in Polydimethylsiloxane
Effective 10 years (approved for 5 years)
Reduces bleeding/infection
LNG-5/10 available in Europe
Clinical applications
To protect the endometrium in: LPD AUB HRT Postponement of menstruation: ( Norethisterone 5 mg tid atleast 3 days prior
to expected date & continued till desired
Menstruation usually starts 48- 72 hrs of withdrawal)
Progestins in LPD & AUB
Dilemmas in diagnosis of LPD LPD causes short luteal phase (irregular
periods) / Infertility / Miscarriage Progestin treatment not evidence based To arrest acute bleeding in AUB,
estrogen is preferred Options: MPA / LNG IUS / OCP / Depot
MPA / Implant
Progestins at Menopause
Required when uterus is intact Androgenic progestin preferred 12-14 days in latter half of cycle. If
erratic or heavy bleeding, increase dose of Progestin
Alternatives: Micronised P / Didrogestone / MPA / LNG / Drosperinone
Progestins in Endometriosis Oral Gastrinone or MPA daily or
Depot MPA monthly: 54% pain relief Continuous COC: better pain control
– Compares with GnRH a LNG IUS same as GnRHa but better
lipids Etonogestrel rod implant: 68% pain
relief over 6 mthsClin NA vol 42 No 1 Mar2015
Progestins in EndometriosisDienogest: 4th Generation progestin Oral 2 mg/day up to 16 months Highly selective for progesterone
receptor Strong progestational & moderate
anti GnH No effect on lipids and BMD Rapid resumption of ovulation
Progesterone in RPL
Progesterone from CL indispensable for progress of pregnancy
Deficiency of P in luteal phase (LPD) causes miscarriage (accounts for >20% of all MC)
No current method to prove P deficiency
Hence P treatment is empirical at best
Progesterone in RPL
Progesterone has no place in natural unstimulated pregnancy but indicated in ART assisted pregnancies
2015 Committee Opinion by the Am Soc of Repr Med
May be tried in RPL (>3) empirically after FH detected until 8-10 weeks of gestation. (Evidence poor)
(Clin N Am, Mar 2015 Vol 42 No 1)
Oral or Vaginal? – Issue not resolved Results of PROMISE Trial awaited
Progestins to prevent PTL
Progestins achieve uterine quiescence in the second half of pregnancy
Hydroxy progesterone caproate (FDA-approved) or Micronised progestins preferred
Limits production of PG and inhibits contraction- associated protein genes , oxytocin, PG receptors & gap junctions within the myometrium
Rev Obstet Gynecol. 2011 Summer; 4(2): 60–72
Other uses
Progesterone receptor antagonist or selective progesterone receptor modulators (SPRM)s RU -486 used to prevent conception or induce medical abortion.
Progesterone is sometimes used as a component for the treatment of male to female dysphoria.
Non gynecological uses
Progesterone is being investigated as potentially beneficial in treating multiple sclerosis
Progesterone has a protective effect on damaged brain by reducing the inflammation that follows brain trauma
Progesterone is starting to be used in the treatment of the skin condition hidradenitis suppurativa
Wish you a fruitful CME & grand success in examination!