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!