B-23. Progestins And Antiprogestins. Flashcards
What is the natural progestin and where is it produced? Pharmacokinetic and administration?
Progesterone, produced by corpus luteum Orally ineffective (first pass metabolism) → i.m. administration
Physiological effects of progesterone
Physiological effects (IC receptors – gene expression):
▪ Main action: inhibit proliferation, promote differentiation (except breast – they have involvement in proliferation as well), cooperation with estrogens
▪ Endometrium: maturation and secretory changes following
ovulation
▪ Breast: proliferation, then alveolobuar development of the
secretory apparatus
▪ Implantation, maintenance of pregnancy, inhibition of ovulation
▪ Increase of body temperature
▪ Metabolic effects: fat deposition, effects of carbohydrate
metabolism, ketogenesis
▪ Competition with aldosterone receptor (decreased sodium
reabsorption)
▪ Respiratory effect: ventilator response to CO2 is increased
▪ Depressant and sedative/hypnotic effect on the brain
▪ Increased urinary N excretion (catabolic effect)
Synthetic progestins pregnans
Hyroxyprogesterone medroxyprogesterone megestrol drospirenone (Closely related to progesterone)
Why are synthetic progestins better?
Better oral bioavailability
Estrans (19-nonsteroids)
Norethisterone
Norethynodrel
Ethynodiol
Lynestrenol
Function of Estrans (19-nonsteroids)
Norethisterone, norethynodrel, ethynodiol, lynestrenol
▪ Do not support pregnancy, produce non-physiological changes of the endometrium, inhibit implantation, more effective
gonadotropin inhibitors
▪ Androgen/anabolic action
Gonans (13-ethyl derivatives of 19-nonsteroids)
Norgestrel
Desogestrel
Norgestimate
Gestodene
Clinical uses of progestins
Clinical uses of progestins
- Primary hypogonadism:
o Hormone replacement therapy (combination with estrogens)
- Postmenopausal hormone therapy (to reduce risk of endometrial cancer caused
by estrogens)
- Hormonal contraception
- Long-term ovarian suppression
o Treatment of dysmenorrhea, endometriosis, bleeding disorders when
estrogens are contraindicated
- Palliative treatment of estrogen-dependent tumors
- Medroxyprogesterone:
o Prevent menstruation but does not arrest bone maturation in children
with precocious puberty
Adverse effects of gestagens
Adverse effects of gestagens
- Increased risk of breast cancer
- Decreased HDL
- Impairment of glucose tolerance
- Elevation of blood pressure
- Headache, psychic disturbances
- Androgenic/anabolic adverse effects of 19-norsteroids
Progesterone antagonist drugs
Mifepristone
Ulipristal
Mifepristone Indication? Adverse effects? Activity? Potential indications?
Mifepristone
o 10-norsteroid, progesterone receptor antagonist (SPRM?) o Terminates early pregnancy (in combination with vaginal PGE1 or with
its analogue misoprostol p.o.)
o Adverse effects of the combination:
▪ Vomiting, diarrhea, abdominal pain, vaginal bleeding
o Antiglucocorticoid activity
o Potential indications:
▪ Endometriosis, breast cancer, meningioma
Ulipristal indication
Ulipristal:
o Morning after pill
o Treatment of myomas
Postmenopausal hormonal therapy therapeutic goal
Postmenopausal hormonal therapy
- Therapeutic goal:
o Symptomatic relief of atrophic vaginitis and other local problems by local use of estrogens
o Symptomatic relief of hot flushes, sweating, insomnia, climacteric
psychopathological states (mental depression) with a short-term
hormonal therapy
o Long-term prevention and treatment of osteoporosis
Postmenopausal hormonal therapy treatment? Estrogen effect? Adverse effect?
Postmenopausal hormonal therapy
-Usually the treatment is very effective
- Estrogens alone relieve the symptoms, but in case of systemic use and intact uterus progestins are added to reduce the risk of endometrial cancer - Adverse effects:
o Local and short-term systemic treatment is less problematic
o Chronic systemic postmenopausal hormone replacement increases the
risk of cardiovascular complications and breast cancer
