1. PROGESTERONE
Narayanan R
ObGyan 2015

2. 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

3. 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.

4. 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.

5. 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  ng/ml at term.

6. Pharmacokinetics: Used for detection of ovulation(urinary metabolite)
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 circulation
T1/2 -30 min
Reaches base line in 12 hrs
Peak levels in 2 hrs
So requires BD dosage

7. 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

8. Structarally related to progesterone
Classification
Progestins
Synthetic
Natural
Structarally related to progesterone
Structurally related to testosterone
Progesterone

9. Related to progesterone
Pregnane derivatives
19-norprogesterone derivatives
Acetylated MPA
Megesterol acetate
Cyproterone acetate
Chlormadinoneacetate
(minipill)
Acetylated MPA
Megesterol acetate
Cyproterone acetate
Chlormadinoneacetate
(minipill)
Nonacetylated
Dydrogesterone (duphaston)
Nonacetylated
Dydrogesterone (duphaston)
Demegestone
Nomegesterol
Nestrone
drosperinone

10. Related to testosterone Ethinylated Dienogest
Nonethinylated
Norethindrone lynestrenol
Norethinsterone (primolut-N)
NORETHINSTERONE ACETATE (REGESTERONE)
Gonanes
LNG (OVRAL)
Desogestrel
Gestodone
norgestimate
Dienogest

11. 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.

12. 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.

13. Estrane (I Generation): norehisterone, norethynindiol Gonane (II Generation): levonorgestrel, norgestrel Their strong inhibitory action on pituitary gonadotrophins and hemostatic activity make them effective contraceptives.

14. III Generation : Desogestrel, gestodene, norgestimate They are lipid friendly & potent antiovulatory. IV Generation: Drospirenone, dienogest, nomegestrol Increased risk of thrombosis

15. 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

16. Clinical Applications

17. 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

18. 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

19. 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. 

20. Contraception: Progesterone contributes by:
Inhibiting ovulation by inhibiting LH surge
Making cervical mucus thick
Making endometrium non receptive for implantation. 

21. Evolution 1960s EE 50mcg+NEa 4mg 2000 1960s EE 30/20 Drospirenone
Norgestrel
Levonogestrel
2009
Estradiol valerate+
Dienogest
1970s
Minipill - POP
LevoNG 30mcg
1990s
E40%+LevoNG
E is the active component-Thrombitis-Reduction in EE to reduce SE- POP spotting
– Triphasic poor control
– Dros+antiminerelocorticoid/less SE/more VTE/24+4
–Qlaira: natural E2/Unique dosage 26+2
1970s
Micropill
EE30mcg+LevoNg150
1970s
Triphasic Pill 21

22. 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

23. Extended Regimens:

24. 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

25. 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

26. 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 

27. 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

28. 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 hrs of withdrawal)  

29. 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
Pulsatile P levels fluctuate
Short luteal phase-s progesterone-EB dating: art not science
Experience based not evidence based

30. 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

31. 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 mths
Clin NA vol 42 No 1 Mar2015

32. Progestins in Endometriosis
Dienogest:
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

33. 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

34. 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
Iatrogenic LPD

35. 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 Summer; 4(2): 60–72

36. 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.

37. 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

38. Wish you a fruitful CME & grand success in examination!