SM_223b: Reproductive Pharmacology Flashcards
Describe the reproductive axis
Reproductive axis
- Reproductive hormones: GnRH, gonadotropins, estrogen, progesterone, testosterone
- Therapeutic applications: reproductive hormones for therapy, drugs that impact reproductive axis
Describe agonists
Agonist
- Binds receptor
- Physiological conformational change
- Hormone-like physiologic response
Describe antagonists
Antagonist
- Binds receptor
- Non-physiological conformational change
- No physiologic response
Describe selective receptor modulators
Selective receptor modulators
- Tissue-specific agonist or antagonist activity
- Mechanisms: differential expression of receptor in target tissues, differential conformational shape with receptor binding, and differential expression of co-regulators in target tissues
Describe different conformational shapes in binding to the ER
Different conformational shapes in binding to the ER
- ER + estradiol: gene transcription ON
- ER + raloxifene: gene transcription OFF
SERMs activate ____ and ____
SERMs activate co-repressors and co-activators
Describe enzyme inhibitors
Enzyme inhibitors
- Testosterone (biosynthetic pathways): estradiol is a potent estrogen, dihydrotestosterone is a potent androgen
- 5-alpha reductase converts testosterone to dihydrotestosterone, hair follicles in male genitalia
- Aromatase converts androgens to estrogens, in ovary / brain / bone / liver / fat
Prolactin ___ the reproductive axis
Prolactin inhibits the reproductive axis
- Decreased GnRH pulses
- Inhibits LH: no ovulation, inadequate corpus luteum
- Adaptive: avoid pregnancy while lactating
- Treatment goal: decrease prolactin levels
Describe symptoms of hyperprolactinemia
Hyperprolactinemia
- Women: galactorrhea, menstrual irregularity, infertility
- Men: galactorrhea, impotence, visual field abnormalities, headache, extraocular muscle weakness, anterior pituitary malfunction
Dopamine is an endogenous prolactin ___
Dopamine is an endogenous prolactin inhibitor
Dopamine agonists (bromocriptine, cabergoline) ___ and ___
Dopamine agonists (bromocriptine, cabergoline) decrease prolactin secretion and decrease the size of prolactinomas
- Restore menstrual cycles and fertility
- Cabergoline is specific D2 receptor agonist that is long acting and has fewer GI side effects
Polycystic ovary syndrome results from ___
Polycystic ovary syndrome results from excess androgen from the ovary
- Follicles do not convert from androgenic to estrogenic milieu
- Dominant follicle is not selected
- No ovulation
- Treatment goal: increase FSH to increase aromatase, decrease testosterone
Describe actions of clomiphene citrate
Clomiphene citrate
- Increases endogenous estrogen
- Anti-estrogen in brain, cervical mucus, endometrium
- Leads to increased FSH due to perceived low estrogen, stimulates follicles (may be > 1), increases estrogen, causes ovulation
Describe actions of tamoxifen
Tamoxifen
- Reduces incidence of breast cancer
- Also induces ovulation
- Biological action depends on cell type
- Anti-estrogenic in breast, leads to hot flashes
- Estrogenic: venous thrombosis, maintains bone density, vaginal mucosa, endometrium (increases risk of endometrial cancer)
Describe actions of aromatase inhibitor
Aromatase inhibitor
- Blocks estrogen production: decreases negative feedback, leads to increased FSH -> follicle development
- Adjuvant treatment for breast cancer
- Short half-life and decreased anti-estrogenic effects (better endometrium) compared to clomiphene
Insulin ____ androgen production from theca cells, particularly in PCOS patients
Insulin increases androgen production from theca cells, particularly in PCOS patients
____ is best for ovulation induction in PCOS
Clomiphene plus metformin is best for ovulation induction in PCOS
Anovulation with PCOS has clinical consequences of ____, ____, and ____
Anovulation with PCOS has clinical consequences of
- Endometrial cancer: due to continuous estrogen without periodic progesterone
- Menstrual disturbances: 50% amenorrhea, 30% dysfunctional uterine bleeding
- Infertility
Estrogen peaks in ____, while progesterone peaks in ____
Estrogen peaks in proliferative / follicular phase, while progesterone peaks in secretory / luteal phase
Medroxyprogesterone acetate is a ___ used for ___ or ___
Medroxyprogesterone acetate is a progestin used for cycle control (5-10 day course) or contraception (Depo-Provera)
Birth control pills consist of ___ or ___ and exert ___ feedback
Birth control pills consist of ethinyl estradiol (estrogen) or progestins and exert negative feedback
- Decrease GnRH
- Decrease LH and FSH
Describe oral estrogens for contraception
Oral estrogens for contraception
- Ethinyl group confers oral activity
- Enovid 10
- Ethinyl estradiol
- Estradiol valerate
Describe oral progestins for contraceptions
Oral progestins for contraceptions
- 1st generation (derived from testosterone): norethindrone, norethindrone acetate, ethynodiol diacetate
- 2nd generation (methyl group increased potency): norgestrel and levonorgestrel
- 3rd generation (derived from levonorgestrel, less androgenic): norgestimate, desogestrel
- Drospirenone: spironolactone activity, mild anti-androgen activity
- Dienogest: strong anti-androgenic activity
Combination OCPs consist of ___ and ___
Combination OCPs consist of ethinyl estradiol and progestin
- Reduce ovarian androgen production
- Decrease FSH and LH -> decrease ovarian steroidogenesis
- Estrogen -> increase SHBG -> less free testosterone
- Benefits: reduce acne and hirsutism, cycle control -> reduce risk of endometrial hyperplasia
Menstrual bleeding is ____ and occurs ____
Menstrual bleeding is bleeding in response to ovulation and occurs 14 days later
- In contrast, birth control pills cause hormone withdrawal bleeding
Describe pharmacological effects of progestins in combination oral contraceptive pills
Pharmacological effects of progestins in combination oral contraceptive pills
- Inhibit ovulation by suppressing HPO function
- Diminish ovarian hormone production
- Produce endometrial changes unfavorable for ovum implantation
- Thicken cervical mucus to impede sperm transit
Menopause is ____ and results in ____
Menopause is 1 year after final menses and results in ovarian failure
- Ovarian failure may occur prematurely
Menopause results in ____
Menopause results in estrogen deficiency
- Tissue atrophy: breast, vagina, uterus
- Osteoporosis: bone mineral density, life threatening
Describe treatment for ovarian failure
Ovarian failure treatment
- Hormone therapy: induce puberty if premature ovarian failure, relieve hypo-estrogenic symptoms (hot flashes, vaginal atrophy, maintain bone mineral density)
- Fertility: oocyte donation is needed
Estrogen alone can lead to ____
Estrogen alone can lead to endometrial cancer
Raloxifene is a ___ used for ___ and ___
Raloxifene is a SERM used for osteoporosis or breast cancer
- Biological action depends on cell type
- Anti-estrogenic: breast, hot flashes, vaginal dryness
- Neutral: endometrium
- Estrogenic: venous thrombosis, maintain bone density
Describe the ideal SERM
Ideal SERM
- Anti-estrogen: decrease breast cancer, protect endometrium
- Neutral: venous thrombosis
- Estrogenic: no hot flashes, maintain bone mineral density, and vaginal mucosa
Describe treatment for hypothalamic amenorrhea
Hypothalamic amenorrhea treatment
- Fetility: oral medications usually do not work (trick brain into seeing low estrogen), injections with gonadotropins (FSH and LH) best
- Hormone repalcement: relieve hypoestrogenic symptoms, maintain bone mineral density
Describe dominant follicle selection
Dominant follicle selection
- Day 5-7: decreased FSH
- Most follicles undergo atresia and 1 dominant follicle develops
Describe ovarian follicles by ultrasound
Ovarian follicles by ultrasound
- Normal ovary with 1 dominant follicle and other smaller follicles
- Ovary with many follicles after treatment with gonadotropins
- Gonadotropins in conjunction with IVF: more oocytes -> more embryos
LH surge involves ____ feedback
LH surge involves positive estrogen feedback
- Increased estrogen triggers LH surge
- With IVF: many small follicles, high estradiol
- For IVF: need pituitary suppression, prevent premature LH surge
Describe GnRH regulation of LH and FSH
GnRH regulation of LH and FSH
- Different pulses: amplitude, frequency
- High frequency: favors LH-beta
- Low frequency: favors FSH-beta
- Continuous secretion: desensitization -> decreased FSH and LH
Describe amino acid 6 and 10 positions in GnRH agonists
GnRH agonists
- Amino acid 6 (D-substitution): increases metabolic stability
- Amino acid 10 (ethylamide group): 10x increased affinity for receptors
Desensitization is ___
Desensitization is decreased response with continuous stimulation
- Uncoupling of receptor and signaling pathway
- Downregulation of functional receptors: internalization of receptors (occurs with GnRH agonist)
Describe GnRH agonists
GnRH agonists
- Initial flare before suppression
- May initially worsen symptoms
____ is needed for oocyte maturation because it triggers ____ and ____
LH is needed for oocyte maturation because it triggers ovulation and final maturation (meiosis resumes, cumulus expands)
- No LH commercially available so use GnRH agonist or hCG
hCG is used in assisted reproduction instead of LH because ____
hCG is used in assisted reproduction instead of LH because binds same receptor with long half-life
- hCG other uses are cryptorchidism, male hypogonadism
5 alpha reductase inhibitors ____
5 alpha reductase inhibitors inhibit production of dihydrotestosterone (potent androgen)
- Used for prostate cancer, BPH, male pattern baldness, and hirsutism
Estrogen results in ____ of breast epithelial cells
Estrogen results in proliferation of breast epithelial cells
Describe role of anti-estrogens in breast cancer
Role of anti-estrogens in breast cancer
- Breast cancer prevention: SERMs (tamoxifen, raloxifene)
- Breast cancer treatment: GnRH agonists (goserelin acetate), SERMs (tamoxifen, toremifene), aromatase inhibitors (anastrozole, letrozole)
Describe drugs impacting the reproductive axis and therapeutic uses of reproductive hormones
Drugs impacting the reproductive axis and therapeutic uses of reproductive hormones
