Progestrogens web2

1. Progestogens
Prof.C.Adithan

2. Progestrogens
•Synthesis& secretion
•Main Functions
•Classifications and Preparations
•Therapeutic uses
•Adverse effects
•Pharmacokinetics
Anti-progestrogens: Mifepristone, Ulipristal

3. http://anatomy.iupui.edu/courses/histo_D502/D502f04/lecture.f04/Female04/cycle.jpg
 Secreted from CL
 Under the influence
of LH
 Level declines few
days before next
menstrual cycle

4. LH FSH
Progesterone
Oestrogen

5. Cholesterol
Pregnenolone
Progesterone
21-carbon steroid
17-α- Hydroxy
pregnenolone
17- Hydroxy
progesterone
Dehydro-epi
androsterone
Andro-
stenedione Oestrone
Oestriol
TESTOSTERONE OESTRADIOL

6. Main Functions

7. Main function
Preparation of uterus for nidation & maintenance of pregnancy
Uterus:
 Secretary changes (in the oestrogen primed endometrium)
 If ovum is fertilized
 prepare endometrium
 oxytocin & ergonovine actions
 FSH, LH ovulation
 Cervical secretion – thick, viscid, scanty

8. Vagina: induce pregnancy like changes, leucocyte infiltration
of cornified epithelium
Breast: causes proliferation of acini, Act in concert with
estrogen, to prepare breast for lactation
Body temperature: increased (0.50
C)
Respiration: at higher dose stimulate
Pituitary: weak inhibitor of Gn secretion, Negative feedback
primarily at hypothalamus, reduce the frequency of GnRH
pulse
Metabolism: impair glucose tolerance,
19-nortestosterone derivati: LDL and HDL

9. Classifications and
Preparations

10. Classification by Generation
Classificatio
n by
structure
First Second Third
Estranes Ethynodiol
diacetate
— —
Norethindrone
Norethindrone
acetate
Gonanes Norgestrel Levonorgestrel Desogestrel
Gestodene
Norgestimate
Pregnanes Medroxyprogeste
rone acetate
— —

11. Natural progesterone
obtained from soybeans and Mexican yam roots, and
animal ovaries (often).
Progesterone derivatives (C-21 steroid structures)
Hydroxyprogesterone caproate (i.m)
Medroxyprogesterone Acetate (im,Oral)
Megesterol Acetate (oral)
Dydrogesterone (oral)
Almost Pure progestins
Weaker anti-ovulatory action

12. Nomegesterol (oral microionized natural progesterone)
Weak antiandrogenic, Less anti-ovulatory, Strong
antioestrogenic
Micronizing process increase the half-life of progesterone
and reduce its destruction in the GIT and Maxium serum
conc. achieved rapidly
Absorption 2 fold increased when taken with food.
No Adverse effects on mood, lipid profile, glucose
tolerance and pregnancy outcome
Common side effects: Fatigue and Sedation.

13. 19-Nor-testosterone derivative
Older Compounds
 Norethindrone
 Lynestrenol (Ethinyl
oestradiol)
 Allylestrenol,
 Additional weak oestrogenic,
androgenic and anabolic
 potent anti-ovulatory actions
19-Nor-testosterone derivatives: (Gonanes)
Levonorgestrel, Desogestrel, Norgestimate, Gestodene
 All are given orally
 Very potent progestins,
 No androgenic effects, Strong anti-ovulatory actions
 Used in OCS
 Do not antagonize the beneficial effects of estrogens on lipid
profile
 Suitable for women with hyperandrogenemia

14. Synthetic Progestins (Except Gonanes) Vs Natural Progestins
Androgenic effects of synthetic progestins include
fluid retention,
reduction of HDL cholesterol levels,
headaches and
mood disturbance.
Some of 19-nortestosterone are strongly
androgenic
Producing hirsutism and acne

15. Transvaginal Progesterone.
•Most practical non-oral route of
administration.
•Produces uterine effects with minimal
systemic side effects.

16. Clinical Uses

17. • OCS: Minipill, Norplant, conventional OCS
• HRT – to antagonize oestrogen side effects, a progestin lacking
androgenic activity is preferred
• DUB: Adolescent, peri/Menopausal women, Norethindrone 20-40
mg/day promptly stops the bleeding, subsequent cyclic treatment with
estrogen
• Endometriosis: presence of ectopic endometrial cells outside
the uterus, continue to respond to O and P, cause dysmenorrhea, painful
pelvic swelling, infertility.
• Goal of therapy is to induce estrogen poor environment, Continued
admn. of P induces anovulatory, estrogenic poor state by GnRH
• Dysmenorrhea
Clinical uses of Progesterones

18. • Premenstrual syndrome: suppress ovulation (O + P)
• Threatened abortion: only P deficiency cases: pure
P without androgenic and oestrogenic preferred
• Post-partum lactation
• Endometrial cancer: palliative, high dose required
• Hypoventilation
Clinical uses of Progesterones

19. Adverse Effects

20. Adverse effects of Progesterone
• breast engorgement, headache, rise in body
temp, oedema, acne & mood swings
• masculinization of external genitalia in the
foetus
• Increased incidences of congenital
abnormalities
• irregular bleeding or amenorrhea
• lower HDL (19-nortestosterone derivatives)
• hyperglycaemia

21. Pharmacokinetics

22. Pharmacokinetics
•Absorption:
• progesterone undergoes high first pass metabolism.
Therefore synthetic preparations are commonly used.
• Progesterone esters in oily soln. for i.m. admn.
•Metabolism:
• by liver enzymes
• excretion by urine after conjugation

23. Antiprogestins

24. Antiprogestin
Mifepristone
19-norsteroid derivative
Potent anti-progestin
has anti-glucocorticoid and antiandrogen action

25. Mifepristone
Given during
Follicular phase:midcycle surge of Gn from Pituitary
slow follicular development, ovulation
Luteal phase: prevents secretary changes on endometrium

26. Mifepristone
Mechanism:
• Partial agonist, progesterone receptor modulator
• During luteal phase: Block Pregest. PGs Uterine
contraction
• Sensitize myocardium to PGs. Induce menstruation
• HCG production falls, secondary luteolysis, softening of cervix
leading to abortion
ADME:
• F: 25 %, CYP3A4 metabolism, t½: 20 h

27. Uses:
• Termination of early pregnancy – along with
prostaglandin (upto 7 weeks), 600 mg single oral + 400 mg
oral misoprotol or 1mg gemeprost intravaginally
• As a cervical ripening agent: surgical abortion
• Post-coital contraceptive: within 72 hours
• Once a month contraceptive: 200 mg at 2 days after
midcycle of ovulation
• Progesterone sensitive tumors
• Cushing’s syndrome

28. Side effects:
Vomiting, diarrhoea,
pelvic pain or abdominal pain,
about 5% have severe vaginal bleeding
Precaution: Not to be given to a woman with suspected
ectopic pregnancy, hematological disorders, receiving oral
anticoagulants, Liver/renal diseases

29. Ulipristal
• Selective progesterone receptor modulator (SPRM)
• Used in emergency contraceptive (within 5 days, 30 mg)
• Inhibits ovulation by LH surge + direct effect on follicule
• By its action on endometrium, inhibits implantation
• Weaker anti-glucocorticoid activity
• Metabolised by CYP3A4 and drug interaction possible with
rifampicin, phenytoin, carbamazepine
OTHERS:
Onapristone (pure progesterone antagonist) ,
Gestinone (more effective in endometriosis)

30. Thank you