female reproductive endocrinology, 9. Estrogens and antiestrogens, 10. Progestins and antiprogestins 11. Contraceptives Flashcards
ovarian hormones- estrogen
ovarian hormones
- Female reproductive development and function – growth of genital structure, appearance of secondary sexual characteristics, growth spurt during puberty
- Metabolic effects – modifies protein levels, TG ↑, LDL ↓, HDL ↑
- Blood coagulability ↑, bone resorption ↓
estrogens:
- ethinyl-estradiol
- mestranol
conjugated estrogen: (premarin), - estradiol
Side effects – Estrogens:
- Moderate - toxicity
- Breast tenderness
- Breakthrough bleeding
- Nausea
- Severe toxicity
- Thromboembolism
- Gallbladder disease
- Hypertriglyceridemia
- Migraine
- Hypertension
- Depression
- In postmenopausal women
- Breast cancer
- Endometrial hyperplasia + cancer
- Increased risk of cardiovascular events
*In hypogonadal girls
Dosage should be adjusted to prevent premature epiphyseal closure of long bones (subsequent short stature)
Anti-estrogens
SERM= selective estrogen receptor modulators
- estrogen antagonist - breast, CNS, uterus
- estrogen agonist - liver, bone
Tamoxifen
Raloxifene
Clomifene
estrogen-receptor-antagonist: Fulvestrant
Synthesis inhibitors:
aromatase inhibitors: Anastrozole (Letrozole, Exemestane)
(Cyp450 inhibitor: danazol)
GnHR analogue
(Leuprolide)
Groserelin
continious stimulation suppresses GnHR release- estrogen–, progesterone–
GnHR antagonist
Degarelix
gamirelix
Ovarian hormones- progesterone
Progestins:
- Pregans
- Estrans
- Gonans
- Pregans:
a) medroxyprogesterone-acetate
b) Cyproterone acetate
b) Drospirenone (Drospirone??) - Estrans:
a) Norethisterone - Gonans:
a) levonorgestrel
b) desogestrel
- Induce secretory changes in the endometrium, breast proliferation
- Maintenance of pregnancy
- Metabolic effects (modify carbohydrate metabolism, stimulate fat deposition)
Side effects – Progestins:
- HDL↓,LDL↑
- Hypertension
- Weight gain
- Reversible decrease of bone density
- Breast cancer risk ↑
Anti-progestins
Mifepristone
- (combined with Misoprostol for abortion)
- glucocorticoid-R-antagonist
- progestin-R-antagonist
Ulipristal acetate
- SPRM- selective progestin receptor modulator
- Emergency birth pill
- (or high level of Levonorgestrel)
Contraceptive
1-2-3 phases
Ethinyl-estradiol
+
Levonorgestrel or desogestrel or Drospirenone or Norethisterone or cyproterone acetate
Ethinyl-estradiol
Mestranol
Estrogens
- Female reproductive development and function – growth of genital structure, appearance of secondary sexual characteristics, growth spurt during puberty
- Metabolic effects – modifies protein levels, TG ↑, LDL ↓, HDL ↑
- Blood coagulability ↑, bone resorption ↓
- Synthetic estrogen, improved bioavailability
- Oral, parenteral, transdermal patch
- Metabolism by hepatic CYP450
- Interaction with P450 inducers may lead to bleeding and reduced
contraceptive efficacy - Hypogonadism in girls
- Hormone replacement therapy
- Prevent bone loss and osteoporosis
- Oral hormonal contraceptives
- Parenteral contraceptive
Side effects – Estrogens:
- Moderate - toxicity
- Breast tenderness
- Breakthrough bleeding
- Nausea
- Severe toxicity
- Thromboembolism
- Gallbladder disease
- Hypertriglyceridemia
- Migraine
- Hypertension
- Depression
- In postmenopausal women
- Breast cancer
- Endometrial hyperplasia + cancer
- Increased risk of cardiovascular events
*In hypogonadal girls
Dosage should be adjusted to prevent premature epiphyseal closure of long bones (subsequent short stature)
Conjugated estrogen (Premarin) - Estradiol
Estrogens
- Female reproductive development and function – growth of genital structure, appearance of secondary sexual characteristics, growth spurt during puberty
- Metabolic effects – modifies protein levels, TG ↑, LDL ↓, HDL ↑
- Blood coagulability ↑, bone resorption ↓
- Conjugated estrogen (estradiol) of biological source
- Oral, parenteral, transdermal patch
- Hypogonadism in girls
- Hormone replacement therapy (premature ovarian
failure, menopause, surgical removal of ovaries) - Prevent bone loss and osteoporosis
Side effects – Estrogens:
- Moderate - toxicity
- Breast tenderness
- Breakthrough bleeding
- Nausea
- Severe toxicity
- Thromboembolism
- Gallbladder disease
- Hypertriglyceridemia
- Migraine
- Hypertension
- Depression
- In postmenopausal women
- Breast cancer
- Endometrial hyperplasia + cancer
- Increased risk of cardiovascular events
*In hypogonadal girls
Dosage should be adjusted to prevent premature epiphyseal closure of long bones (subsequent short stature)
Tamoxifen
SERM – Selective estrogen receptor modulators
- Estrogen antagonist activity → breast, CNS, uterus
- Estrogen agonist activity → liver, bone
- Oral
- Partial agonist in the endometrium
- Hormone-responsive breast cancer (also as prophylaxis)
- Side effects:
hot flushes,
thromboembolism,
endometrial hyperplasia
Raloxifene
SERM – Selective estrogen receptor modulators
- Estrogen antagonist activity → breast, CNS, uterus
- Estrogen agonist activity → liver, bone
- Oral
- Treatment and prevention of osteoporosis in postmenopausal women
Clomifene
SERM – Selective estrogen receptor modulators
- Estrogen antagonist activity → breast, CNS, uterus
- Estrogen agonist activity → liver, bone
- Oral
- Ovulation induction
(selectively inhibits estrogen receptors in pituitary → reduced negative feedback → increased LH and FSH)
Fulvestrant
not on the list
Estrogen receptor antagonists
- Non-selective antagonist
- Intramuscular injection
- Breast cancer resistant to 1st line tamoxifen
- Side effects: hot flushes, headache, injection site
reaction
Anastrozole
Synthesis inhibitors
Aromatase inhibitors
(- Letrozole (non-steroidal))
(- Exemestane (steroidal))
- Anastrozole
- Oral
- Adjuvant treatment of hormone-responsive breast cancer (advanced disease)
- anticancer
- Side effects:
- hot flushes,
- musculoskeletal disorders,
- reduced bone mineral density,
- joint symptoms
- Nausea, vomiting, diarrhea
Danazol
not on the list
synthesis inhibitor:
- CYP450 inhibitor, partial agonist of progestin and androgen receptors
- Oral
- Endometriosis
- Fibrocystic breast disease
- Side effects: acne, hirsutism, weight gain, menstrual
disturbances, hepatic dysfunction
Goserelin
Leuprolide
- Synthetic peptide with GnRH agonist activity
- Parenteral
- Long-acting
- Continuous administration of GnRH agonists suppresses gonadotropin secretion and thereby inhibits ovarian production of estrogens and progesterone
→ inhibits the release of FSH and LH → both androgen and estrogen syntheses are reduced
indications:
- Ovarian suppression in women undergoing controlled ovulation induction
- Ovarian suppression in endometriosis, leiomyoma
- Central precocious puberty
- Prostate cancer
- Breast cancer
Side effects:
- headache,
- nausea,
- injection site reaction,
- symptoms of hypogonadism with continuous treatment (impotence in male)
Degarelix
Ganirelix
Degarelix
- GnRH antagonist
- Parenteral
- GnRH receptor inhibition → altered release FSH and LH → testosterone synthesis ↓
- Prostate cancer
- Controlled ovarian stimulation (suppress endogenous LH and FSH) (1st stage)
Side effects:
- Nausea, vomiting
- Headaches
Progesterone
- Low oral bioavailability
- Biologic source
- Induce secretory changes in the endometrium, breast proliferation
- Maintenance of pregnancy
- Metabolic effects (modify carbohydrate metabolism, stimulate fat deposition)
Side effects – Progestins:
- HDL↓,LDL↑
- Hypertension
- Weight gain
- Reversible decrease of bone density
- Breast cancer risk ↑
Pregnans
Medroxyprogesterone
Drospirone
Cyproterone acetate
Estrans
Norethisterone
Gonans
Norgestrel
Desogestrel
Medroxyprogesterone
Progestins
- Induce secretory changes in the endometrium, breast proliferation
- Maintenance of pregnancy
- Metabolic effects (modify carbohydrate metabolism, stimulate fat deposition)
PREGANS
- Synthetic progesterone
- Improved oral bioavailability
- Metabolism by hepatic CYP450
- Hormone replacement therapy
- Hormonal contraceptives
- Infertility treatment
- Prevent estrogen-induced endometrial cancer
- Assisted reproductive technology methods
(promote and maintain pregnancy)
Side effects – Progestins:
- HDL↓,LDL↑
- Hypertension
- Weight gain
- Reversible decrease of bone density
- Breast cancer risk ↑
Drospirone / Drospirenone
Progestins
- Induce secretory changes in the endometrium, breast proliferation
- Maintenance of pregnancy
- Metabolic effects (modify carbohydrate metabolism, stimulate fat deposition)
PREGANS
- Synthetic progesterone
- Improved oral bioavailability
- Metabolism by hepatic CYP450
- Hormone replacement therapy
- Hormonal contraceptives
- Infertility treatment
- Prevent estrogen-induced endometrial cancer
- Assisted reproductive technology methods
(promote and maintain pregnancy)
Side effects – Progestins:
- HDL↓,LDL↑
- Hypertension
- Weight gain
- Reversible decrease of bone density
- Breast cancer risk ↑
Cyproterone acetate
Progestins
- Induce secretory changes in the endometrium, breast proliferation
- Maintenance of pregnancy
- Metabolic effects (modify carbohydrate metabolism, stimulate fat deposition)
PREGANS
- Synthetic progesterone
- Improved oral bioavailability
- Metabolism by hepatic CYP450
- Hormone replacement therapy
- Hormonal contraceptives
- Infertility treatment
- Prevent estrogen-induced endometrial cancer
- Assisted reproductive technology methods
(promote and maintain pregnancy)
Side effects – Progestins:
- HDL↓,LDL↑
- Hypertension
- Weight gain
- Reversible decrease of bone density
- Breast cancer risk ↑
Norethisterone
Progestins
- Induce secretory changes in the endometrium, breast proliferation
- Maintenance of pregnancy
- Metabolic effects (modify carbohydrate metabolism, stimulate fat deposition)
ESTRANS
- Synthetic progesterone
- Improved oral bioavailability
- Metabolism by hepatic CYP450
- Hormone replacement therapy
- Hormonal contraceptives
- Infertility treatment
- Prevent estrogen-induced endometrial cancer
- Assisted reproductive technology methods
(promote and maintain pregnancy)
Side effects – Progestins:
- HDL↓,LDL↑
- Hypertension
- Weight gain
- Reversible decrease of bone density
- Breast cancer risk ↑
Levonorgestrel
Progestins
- Induce secretory changes in the endometrium, breast proliferation
- Maintenance of pregnancy
- Metabolic effects (modify carbohydrate metabolism, stimulate fat deposition)
GONANS
- Synthetic progesterone
- Improved oral bioavailability
- Metabolism by hepatic CYP450
- Hormone replacement therapy
- Hormonal contraceptives
- Infertility treatment
- Prevent estrogen-induced endometrial cancer
- Assisted reproductive technology methods
(promote and maintain pregnancy)
Side effects – Progestins:
- HDL↓,LDL↑
- Hypertension
- Weight gain
- Reversible decrease of bone density
- Breast cancer risk ↑
Desogestrel
Progestins
- Induce secretory changes in the endometrium, breast proliferation
- Maintenance of pregnancy
- Metabolic effects (modify carbohydrate metabolism, stimulate fat deposition)
GONANS
- Synthetic progesterone
- Improved oral bioavailability
- Metabolism by hepatic CYP450
- Hormone replacement therapy
- Hormonal contraceptives
- Infertility treatment
- Prevent estrogen-induced endometrial cancer
- Assisted reproductive technology methods
(promote and maintain pregnancy)
Side effects – Progestins:
- HDL↓,LDL↑
- Hypertension
- Weight gain
- Reversible decrease of bone density
- Breast cancer risk ↑
Mifepristone
Anti-progestins
- Progestin and glucocorticoid receptor antagonist
- Oral
- Medical abortion, in combination with prostaglandin-E analogue (Misoprostol); can be used up to 49 days after last menstrual period
- Cushing’s syndrome (not extensively used)
Side effects:
- abdominal pain
- GI disturbances (mostly due to coadministration of misoprostol),
- headache
- vaginal bleeding,
- atypical infection
Ulipristal acetate
Anti-progestins
- SPRM (selective progestin receptor modulator)
- Oral
- Emergency birth pill
- Myoma growth suppression
Hormonal contraceptives - Preparations available + types of oral contraceptives
▪ Preparations available:
- Oral pills
- Long-acting ‘depot’ injections (effective for 8-13 weeks)
- Subcutaneous implants (effective for 3-6 years)
- Transdermal patch (effective for 1 week, can be used 3 weeks in a row)
- Vaginal ring (3 weeks ring in, 1-week break)
- Intrauterine devices – IUD (effective for ∼5 years)
- may also contain spermicidal agent (detergent), provide STD protection
types of oral preparations:
(1) Combinations of estrogens and progestins
(2) Continuous progestin therapy without concomitant administration of estrogens
(also known as the ‘mini-pill’ – progestin only birth control)
Combination agents are further divided into monophasic forms (constant dosage of both components during the cycle) and biphasic or triphasic forms (dosage of preparation components is changed once or twice during the cycle).
Monophasic
Biphasic
(days 1-10, 11-21)
Triphasic
(days 1-7, 8-14, 15-21)
Estrogen component:
Ethinyl-estradiol
Progestin component: Levonorgestrel Desogestrel Drospirenone Norethisterone Cyproterone acetate
Mechanism of action of contraceptives
- Combinations of estrogens and progestins exert their contraceptive
effect through selective inhibition of pituitary function (LH and FSH ↓),
results in inhibition of ovulation (no LH surge) - Some agents also produce changes in the cervical mucosa, uterine
endometrium, and motility and secretion of the uterine tubes; all of which decrease the likelihood of conception and implantation
▪ Further clinical uses and beneficial effects of hormonal contraceptives
- Prevent estrogen deficiency in young women with primary hypogonadism
- Treatment of acne, hirsutism, dysmenorrhea, endometriosis
- Combination hormonal contraceptives reduce the risk of ovarian cysts,
endometrial cancer, benign breast cancer, pelvic inflammatory disease (PID) - Lower incidence of ectopic pregnancies, iron deficiency anemia, and
rheumatoid arthritis
Side effects of hormonal contraceptives
Mild:
- Nausea
- Edema
- Endocrine disturbances
- Headache
- Withdrawal bleeding
Moderate:
- Breakthrough bleeding
- Weight gain
- Skin pigmentation
- Acne
- Hirsutism
- Ureteral dilation
- Vaginal infections
- Amenorrhea
Severe: - Thromboembolism (MI, stroke, DVT, PE) - GI disturbances - Depression - Increased risk of cervical and breast cancer (?)
▪ Contraindications of hormonal contraceptives
- Recurrent thromboembolic/cardiovascular events
- Estrogen-dependent neoplasm
- Vaginal bleeding of unknown origin
- Prior to epiphyseal closure
- Smoking (?)
emergency contraceptive
Postcoital contraceptive (‘emergency contraception’ or ‘morning-after pill’)
Prevent pregnancy if administered within 72 h’ after unprotected intercourse.
Preparations: high-dose progestin (levonorgestrel), or ulipristal acetate (SPEM).
Side effects: nausea, vomiting, headache, breast tenderness, abdominal pain.
