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Progestogens
Prof.C.Adithan
Progestrogens• Synthesis& secretion
• Main Functions
• Classifications and Preparations
• Therapeutic uses
• Adverse effects
• PharmacokineticsAnti-progestrogens: Mifepristone, Ulipristal
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
LH FSH
Progesterone
Oestrogen
Cholesterol
Pregnenolone
Progesterone21-carbon steroid
17-α- Hydroxy pregnenolone
17- Hydroxy progesterone
Dehydro-epi androsterone
Andro-stenedione Oestrone
Oestriol
TESTOSTERONE OESTRADIOL
Main Functions
Main functionPreparation 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
Vagina: induce pregnancy like changes, leucocyte infiltration
of cornified epithelium Breast: causes proliferation of acini, Act in concert with
estrogen, to prepare breast for lactationBody temperature: increased (0.50C)Respiration: at higher dose stimulatePituitary: 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
Classifications and Preparations
Classification by Generation Classification by structure First Second ThirdEstranes Ethynodiol
diacetate — —
Norethindrone Norethindrone acetate
Gonanes Norgestrel Levonorgestrel Desogestrel Gestodene Norgestimate
Pregnanes Medroxyprogesterone acetate
— —
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 progestinsWeaker anti-ovulatory action
Nomegesterol (oral microionized natural progesterone)Weak antiandrogenic, Less anti-ovulatory, Strong antioestrogenicMicronizing process increase the half-life of progesterone and reduce its destruction in the GIT and Maxium serum conc. achieved rapidlyAbsorption 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.
19-Nor-testosterone derivativeOlder 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
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
Transvaginal Progesterone.
•Most practical non-oral route of administration.
•Produces uterine effects with minimal systemic side effects.
Clinical Uses
• 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
• 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
Adverse Effects
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
Pharmacokinetics
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
Antiprogestins
Antiprogestin
Mifepristone19-norsteroid derivativePotent anti-progestin has anti-glucocorticoid and antiandrogen action
MifepristoneGiven duringFollicular phase:midcycle surge of Gn from Pituitary slow follicular development, ovulationLuteal phase: prevents secretary changes on endometrium
MifepristoneMechanism:• 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
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
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
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)
Thank you