B.16 Flashcards
Progestins and antiprogestins. Contraceptives
- (pregnans): Medroxyprogesterone-acetate, Drospirenone, Cyproterone-acetate
- (estrans): Norethisterone
- (gonans): Desogestrel, Levonorgestrel
- Progesterone receptor antagonists: Mifepristone, Ulipristal-acetate
- Oral contraceptive combination: Ethinylestradiol+Levonorgestrel
Contraceptive patches: Estrogen + progestin combinations:
Ethinylestradiol (0.6mg) + norelgestronim
Contraceptive implants:
mplants of norgesterl or etonogestrel (active metabolite of desogestrel)
*DOA: 3-6 years
* low incidence of SEs (low hormonal level): Headache, dizziness, acne, alopecia, mood changes, breast tenderness, decreased libido, weight gain, vasomotor problems, major bleeding disturbances
Local contraceptives
- Intrauterine devices: Levonorgestrel
- Vaginal ring: Ethinylestradiol and etonorgestrel released every day
- Spermicidal disinfectants: Benzalkonium, nonoxinol
Hormonal contraception
- Oral contraception
- Parenteral (depot) contraception
- Transdermal contraceptives
- Contraceptive implants
- Local contraceptives
- Postcoital contraceptives
Morning after pill
- Progestin alone or in combination with estrogen (combo has no beneficial effect over monotherapy)
- within 72h after coitus (best within 12h)
- high dose levonorgestrel
- Common SEs: nausea, vomiting, headache, dizziness, breast tenderness, abdominal and leg cramps
- Ulipristal-acetate
- SPRM, within 5 days (best earlier)
- SEs: similar to progestins
Abortion pill
Mifepristone
Oral Contraceptives
- Estrogen + progestin combination
- Progestins alone (minipill)
- Estrogen + progestin combination
- Monophasic:
Estrogen component: Ethinylestradiol (0.02-0.035mg)
Progestin component: Levonorgestrel (0.1-0.25mg), Norgestimate (0.25), Desogestrel (0.15mg), Gestodene (0.075mg), Chlormadinone (1.71mg), Drospirenone (3mg) - Biphasic: days 1-10, 11-21
Ethinylestradiol (0.03-0.05mg) + Levonorgestrel (0.05→0.125mg) or Desogestrel (0.025→0.125mg)
-Triphasic: e.g. days 1-7, 8-14, 15-21
Ethinylestradiol (0.03→0.04→0.03mg) + gestoden (0.05→0.07→0.1mg) or Levonorgestrel (0.05→0.075→0.125mg)
Effects of oral contraceptives (estrogens+progestins) on sexual organs
- Contraceptive MOA: inhibition of pituitary function, inhibition of ovulation, changes in cervical mucus, endometrium, motility, secretion
- Chronic use depresses ovarian function, and the ovary becomes smaller
- Uterus: Cervix hypertrophy (polyp formation), thicker and less copious cervical mucus, preparations containing 19-norsteroids→ Glandular atrophy less bleeding
- Breast: Enlargement, Suppression of lactation
Side effects of oral contraceptive (estrogen+progestin)
Advantageous SEs:
- Lower incidence of ovarian and endometrial cancer, ovarian cysts
- Less bleeding, lower incidence of anemias
- Improvement of endometriosis, dysmenorrhea
Disadvantageous SEs:
Mild adverse effects→ nausea, edema, mastalgia, endocrine changes, headache, loss of withdrawal bleeding
Moderate adverse effects→ breakthrough bleeding, weight gain, skin pigmentation, acnes, hirsutism, uteral dilation, vaginal infections, amenorrhea
Severe adverse effects→ increased risk of vascular disorders (venous thromboembolism, MI, cerebrovascular disease), Increased risk of GI disorders (cholestasis, gallbladder disease, hepatic adenomas), mental depression, cervical and breast cancer::Mild, Moderate, Severe
Contra-IND of oral contraceptives
- Thrombormbolism, cerebrovascular disorders
- Estrogen-dependent neoplasm
- Vaginal bleeding with unknown origin
- Before the epiphyseal closure is complete
- Progestins alone (minipill):
- Daily progestin tablet: Norethindrone (0.35mg) / norgestrel(0.075mg)
- useful in patients for whom estrogens are undesired or contra-IND (e.g. hepatic disease, prior thromboembolism)
- SEs: Headache, dizziness, weight gain, impaired glucose tolerance, abnormal bleeding
Parenteral (depot) contraceptives
- Injection of depot medroxyprogesterone-acetate (150mg i.m) every 2-3months
*common SEs: Headache, impaired glucose tolerance, disadvantageous lipid change, abnormal bleeding - Can also be injection of combination estrogen+progestin (same as the oral ones)
Postmenopausal hormonal therapy
Therapeutic goal:
- Symptomatic relief of atrophic vaginitis and other local problems by local use of estrogens
- Symptomatic relief of hotflashes, sweating, insomnia, climecteric psychopathologic states (mental depression) with a short-term hormonal therapy
- long term prevention and treatment of osteoporosis
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 effect:
- Local and short term treatment: less problematic
- Chronic systemic postmenopausal hormone replacement increases the risk of the cardiovascular complications and breast cancer
IND of progestins
-Primary hypogonadism (→hormone replacement therapy, combined with estrogens)
-Postmenopausal hormone therapy (to reduce the risk of endometrial cancer caused by estrogens)
-Hormonal contraception:
Long-term ovarian suppression (treatment of dysmenorrhea, endometriosis, bleeding disorders when estrogens are Contra-IND)
-Prevention of preterm birth(?)
-Palliative treatment of estrogen-dependent tumors
SEs of progestins: increased risk of breast cc; ↓HDL; Impairment of glucose tolerance; Elevation of BP; Headache, psychic disturbances; Androgenic/anabolic adverse effects of 19-norsteroids; abnormal bleeding
Medroxyprogesterone-acetate
MOA: Synthetic progestin, Pregnans, closely related to progesterone;
IND: prevent menstruation (but doesn’t arrest bone maturation in children with preterm puberty), p.e (depot) contraceptive, Recurrent/metastatic breast cc (in post menopausal), recurrent/metastatic endometrial cc, recurrent/metastatic renal cc;
Kinetics: can be injected in depot (150mg i.m every 2-3months);
SEs: heat waves, ↓libido, erectile dysfunction, glucocorticoid-like effects, thrombophilia, osteoporosis, edema, hypercalcemia
Drospirenone, Cyproterone-acetate
MOA: Synthetic progestin, Pregnans, closely related to progesterone;
Kinetics: Drospirenone→oral contraceptive, monophasic, combined with Ethinylestradiol (estrogen);
IND: Cyproterone-acetate- inoperable prostate cc;
SEs: thromboembolism, osteoporosis, erectile dysfunction, ↓libido, heat waves
Norethisterone
MOA: Synthetic progestin, Estrans, androgen/anabolic action (do NOT support pregnancy, produce non-physiologic changes of endometrium, inhibit implantation);
IND: Oral contraceptive;
Kinetics: p.o, daily (useful in patients for whom estrogens are undesired or contra-IND (e.g. hepatic disease, prior thromboembolism)
Levonorgestrel, Desogestrel
MOA: Synthetic progestin, Gonans;
IND: oral contraceptive (in combination with estrogen), levonorgestrel (→”morning after” pill), desogestrel (→s.c. contraceptive implants);
Kinetics: p.o adm. in combination with ethinylestradiol, can be monophasic, biphasic (days 1-10, 11-21) or triphasic-only Levonorgestrel (e.g. days 1-7, 8-14, 15-21). Desogestrel s.c. contraceptive implant (DOA: 3-6 years)
Ethinylestradiol + Levonorgestrel
IND: Oral/local contraceptive Kinetics: p.o adm. in combination with ethinylestradiol, can be monophasic, biphasic (days 1-10, 11-21) or triphasic (e.g. days 1-7, 8-14, 15-21).
Can be local contraceptive use-IUD (→DOA: 5 years, daily 20μg release, low systemic hormone levels)
Mifepristone
MOA: 19-norsteroid, progesterone-R antagonist, has antiglucocorticoid activity;
IND: Abortion-pregnancy termination (in combination with vaginal PGE1 or with its analog misoprostol p.o), endometriosis, breast cancer, meningeoma;
SEs: of the combination(→vomiting, diarrhea, abdominal pain, vaginal bleeding)
Ulipristal acetate
MOA: SPRM (progesterone R antagonist);
IND: morning after pill (within 5 days, best earlier), treatment of myomas;
SEs: similar to progestins
SPRM
19-Nor-steroid, progesterone receptor antagonist
Monophasic pills
contain a fixed dose of the same hormones (either estrogen&progestin or just progestin) in each active pill.
Biphasic pills
contain 2 different doses of hormones in each active pill
Triphasic pills
contain 3 different doses of hormones in each active pill
Palliative treatment
a treatment that makes the patient feel more comfortable but doen’t cure the cancer.
The progestins
- Natural progestin: Progesterone, produced by Corpus luteum
- Orally ineffective (first pass metabolism) → i.m administration
- Physiologic effects (intracellular receptors → gene expression)
- main action: inhibit proliferation, promote differentiation
- Endometrium: maturation and secretory changes following ovulation
- Breast: proliferation→ then alveolobular development of the secretory apparatus
- Implantation, maintenance of pregnancy, inhibition of ovulation
- Increase of body temperature
- Metabolic effects: Fat deposition, effects of carbohydrates metabolism, ketogenesis
- Competition with aldosterone receptor → decreased Na reabsorption
- Respiratory effect: ventilatory response to CO2 is increased
- Depressant and hypnotic/sedative effects on the brain
- Increased urinary Nitrogen excretion
- main action: inhibit proliferation, promote differentiation
