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