Medications in REI. Medications in Reproductive Endocrinology

Transcription

1 Medications in REI Bruce Tjaden, D The Center for Reproductive Medicine Reproductive Endocrinology and Infertility Assistant Professor University of Kansas School of Medicine Wichita Dept of B/GYN Division of Reproductive Endocrinology and Infertility

2 cholesterol a H A desmolase B P450 SCC H 3 B ol HSD C 3 B ol HSD H H Pregnenolone 17H Preg DHEAS H H H 21 H ase Progesterone H 17H P4 A dione Testosterone H H 11B H ase Desoxy corticosterone H H Desoxy cortisol H H H H Estrone H Estradiol 17 BHSD 18 H ase Corticosterone H Cortisol Aromatase H = C C = Aldosterone

3 verview Medications name(s) Indications Dosing and prescribing information Side effects Relative information about costs

4 vulation Induction Selective estrogen receptor modulators Aromatase inhibitors Dopamine agonists GnRH agonists & antagonists Insulin sensitizers Progestagens Estrogens Medications in REI

5 vulation induction The final common pathway for all medications used for ovulation induction is to increase the level of FSH in the body!

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7 vulation induction The final common pathway for all medications used for ovulation induction is to increase the level of FSH in the body! Lowering the estrogen signal leads to increased FSH production

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9 Selective estrogen receptor modulators Clomiphene citrate Clomid, Serophene Tamoxifen Nolvadex, Valdox Aromatase inhibitors Letrozole Femara Anastrozole Arimidex Gonadotropins Menotropins (Urinary) Menopur, Pergonal, Bravelle Recombinant FSH Follistim, Gonal-f, LH Luveris Human chorionic gonadotropin (hcg) Urinary Recombinant Profasi, Pregnyl vidrel vulation induction

10 Selective estrogen receptor modulators (SERMS) Clomiphene Tamoxifen Raloxifene Toremifene Bazedoxifene Lasofoxifene spemifene vulation Induction Agonists Antagonists

11 vulation Induction - SERMS Clomiphene citrate (Clomid) Mechanism of action: inhibits the action of estrogen on the gonadotrope cells in the anterior pituitary gland Two (2) isomers ( zu and en ) 50 mg tablets Starting dose 50 mg po qd x 5 days, d3-7 or d5-9 FDA approved to 150 mg po qd Maximal dose 250 mg daily Side effects: Vasomotor hot flushes, irritability 5-10% incidence of endometrial suppression Twin gestation rate ~10% / triplet gestation rate ~ 1-2% Cost: $50-100

12 Tamoxifen Mechanism of action: inhibits the action of estrogen on the gonadotrope cells in the anterior pituitary gland 10 mg tablets Starting dose 10 mg po qd x 5 days, d3-7 or d5-9 Usual maximal dose 20 mg daily Not FDA approved for ovulation induction Side effects: Vasomotor hot flushes, irritability, though less than clomiphene citrate 4-5% incidence of endometrial suppression Twin gestation rate ~10% / triplet gestation rate ~ 1-2% $100 vulation Induction - SERMS

13 Raloxifene (Evista) Indicated for the treatment of osteoporosis in post-menopausal women 60 mg tablets Dose: 60 mg po qd Side effects: Vasomotor hot flushes, leg cramps Favorable lipid changes?? Increase in thrombo-embolic events SERMS

14 spemifene (sphena) SERMS The only oral, non-estrogen treatment FDA-approved for moderate to severe dyspareunia

15 SERMS Bazedoxifene In conjunction with CE is FDA approved for use To treat vasomotor hot flushes To prevent osteoporosis No need for a progesterone Tissue selective estrogen complex pair a specific SERM with a specific systemic estrogen (BZA / CE)

16 vulation Induction - AI Aromatase inhibitors (overview) Inhibit the conversion of testosterone to estradiol and androstenedione to estrone by inhibiting aromatase Type I Irreversible steroidal inhibitors Exemestane Type II Reversible non-steroidal inhibitors Letrozole Anastrozole

17 cholesterol a H A desmolase B P450 SCC H 3 B ol HSD C 3 B ol HSD H H Pregnenolone 17H Preg DHEAS H H H 21 H ase Progesterone H 17H P4 A dione Testosterone H H 11B H ase Desoxy corticosterone H H Desoxy cortisol H H H H Estrone H Estradiol 17 BHSD 18 H ase Corticosterone H Cortisol Aromatase H = C C = Aldosterone

18 Letrozole (Femara) 2.5 mg tablets Starting dose 2.5 mg po qd d3-7 Maximal dose is unknown (?? 7.5 mg po qd??) ther regimens: 20 mg on cd 2 or 10 mg po qd d2-3 NT FDA approved for ovulation induction Multiple gestation rate ~ 10% Side effects: hot flushes, headaches, nausea, adverse lipid effects ther indications: endometriosis, pelvic pain, endometrial hyperplasia (??), any hyper-estrogenic state Cost ~ $100 vulation Induction - AI

19 Anastrozole (Arimidex) 1 mg tablets Starting dose 1 mg po qd d3-7 Maximal dose is unknown Dosing studies are ongoing at this time NT FDA approved for ovulation induction Multiple gestation rate?? probably ~ 10% Side effects: hot flushes, joint symptoms vulation Induction - AI

20 vulation Induction - Gonadotropins Urinary gonadotropins = Menotropins Recombinant gonadotropins

21 vulation Induction - Gonadotropins Menotropins The original FSH drug -- PERGNAL Derived from urine of post menopausal women Contains both FSH and LH (~50/50) Bravelle, Menopur Indicated for CC failures and patients with hypothalamic hypogonadism Costs ~ $100 / day

22 vulation Induction - Gonadotropins Menotropins IM injection Lyphilized, dispensed in ampules, each containing 75 IU (international units) Usual starting dose 150 IU daily Duration of therapy varies but is usually 8-10 days Sonography and serum estradiol are used to monitor the course Generally well tolerated with few side effects Twin pregnancy rate ~ 30-40%; triplets and higher ~ 5-8% varian hyperstimulation syndrome occurs in 1-2% of the cycles

23 Recombinants vulation Induction - Gonadotropins Made using recombinant DNA technology IS NT a human by product Contains only FSH Follistim and Gonal-f Indicated for CC failures and patients with hypothalamic hypogonadism Costs ~ $ 150 / day

24 vulation Induction - Gonadotropins Recombinants Sub cutaneous injection Dispensed in self injecting PEN in (international units) Usual starting dose 150 IU daily Duration of therapy varies but is usually 8-10 days Sonography and serum estradiol are used to monitor the course Generally well tolerated with few side effects Twin pregnancy rate ~ 30-40%; triplets and higher ~ 5-8% varian hyperstimulation syndrome occurs in 1-2% of the cycles

25 vulation Induction - Gonadotropins LH Made using recombinant DNA technology IS NT a human by product Contains only LH Luveris (lutropin alfa) Indicated for use in ovulation in patients with hypothalamic hypogonadism to be used in conjunction with FSH

26 LH surge

27 vulation Induction - Gonadotropins Human chorionic gonadotropin (hcg) Used as a surrogate for LH Used to trigger ovulation (36 hours after injection) Longer half life than LH Urinary Profasi, Pregnyl, Novarel Dispensed in lyophilized vial, 10,000 Units IM injection Recombinant vidrel (choriogonadotropin alfa injection) Sub cutaneous injection Dispensed in vials, pre-fill syringe, 250 ug

28 Dopamine agonists PRL is produced & secreted by the lactotroph cells of the anterior pituitary gland. Secretion of PRL is regulated primarily by the inhibitory effects of the hypothalamus rather than the stimulatory effects, unlike other pituitary hormones. Dopamine is the predominant inhibitory factor. HyperPRL results when the dopamine effect is decreased. DA GABA PIF lactotrope receptors TRH VIP Angiotensin II PRF PRL release tonic pulsatile estradiol progesterone

29 Dopamine agonists Bromocriptine (Parlodel) Dispensed as 2.5 mg tablets Indicated for hyperprolactinemia adenomas, Parkinson s disease Starting dose 2.5 mg po qd at HS Effective dose 5 mg po qd Can be prescribed bid Side effects nausea, nasal congestion, headache, dizziness, postural hypotension Vaginal administration usually decreases side effects Should not be used for suppression of post partum lactation HN Br C CH(CH 3 ) 2 H CH N N N N CH CH 2 CH(CH 3 ) 2 bromocriptine

30 Dopamine agonists Cabergoline (Dostinex) Dispensed as 0.5 mg tablets Approved for hyperprolactinemia adenomas but NT Parkinson s disease Starting dose 0.25 mg po twice weekly Effective dose 0.50 mg po twice weekly Side effect profile is the same as Parlodel though fewer patients are affected nausea, nasal congestion, headache, dizziness, postural hypotension Vaginal administration usually decreases side effects N H H CH 3 CH 2 CH 2 CH 2 N - CH 3 C - N - CNH- CH 2 CH 3 N - CH 2 - CH = CH 2 H cabergoline

31 Dopamine agonists Pergolide (Permax) Pulled from the US market secondary to study published in the NEJM Jan 07 linking pergolide AND cabergoline to vavular heart disease CH 3 CH 2 CH 2 CH 2 N - CH 3 C - N - CNH- CH 2 CH 3 As cabergoline is not approved for Parkinson s and the dose for hyperprolactinemia from adenomas is significantly lower than that for Parkinson s cabergoline HAS NT been pulled from the US market N H H N - CH 2 - CH = CH 2 H cabergoline

32 GnRH 10 amino acid peptide GnRH Agonists and Antagonists Secreted by the hypothalamus in a pusatile fashion Stimulates the release of gonadotropins (FSH and LH) Pulse frequency and amplitude vary during the day and during the cycle

33 GnRH Agonists and Antagonists GnRH GnRH receptor Pulsatile GnRH Continuous GnRH or GnRH-a protein kinase - C protein-p 4 nucleus Ca ++ Ca ++ FSH LH Ca ++ + calmodulin FSH LH FSH / LH FSH / LH

34 GnRH Agonists and Antagonists Agonists Binds to pituitary GnRH receptors Do not dissociate from the GnRH receptor leading to a stimulation of the receptor with release of gonadotropins Prolonged binding and stimulation leads to exhaustion of the gonadotrope cell leading to marked decrease in output of gonadotropins Alterations at the 6 and 10 positions significantly prolong half-life Suppression of pituitary gonadotropin release takes ~ 10 days. FDA approved for prostate cancer, endometriosis, uterine myomata and central precocious puberty

35 Agonist GnRH Agonists and Antagonists Substitutions at the 6 & 10 positions Leuprolide (Lupron) Buserelin (Suprefact) Narafelin (Synarel) Histrelin (Supprelin) Goserelin (Zoladex) Deslorelin Substitution at the 6 position Triptorelin

36 GnRH Agonists and Antagonists Agonist Parenteral or intra-nasal Daily, monthly, quarterly preparations Most widely prescribed is Lupron ~ $800 / month

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39 Change in myoma size w/ LA treatment 40% decrease in VLUME with LA initial diameter 40% decrease in diameter initial radius volume change after LA radius after LA diameter after LA

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42 GnRH Agonists and Antagonists Antagonist Parenterally active only Multiple AA substitutions Blocks the receptor and decreases gonadotropin output within hours No FLARE effect Indications: inhibition of premature LH surges in women undergoing controlled ovarian hyperstimulation Activity is short-lived, necessitating daily injection Ganirelix (Antagon) 0.25 mg (daily) Cetrorelix (Cetrotide) 0.25 mg (daily) and 3.0 mg (lasts 4 days)

43 Insulin sensitizing agents Biguanide Metformin (Glucophage) Thiazolidinedione Rosiglitazone (Avandia) Pioglitazone (Actos)

44 Metformin Exact mechanism of action is unknown Reduces hepatic gluconeogenesis, increases insulin sensitivity and decreases glucose absorption from the GI tract Approved for treatment of NIDDM, especially in conjunction with obesity and insulin resistance (IR) Used extensively in non-diabetic PCS patients with IR Usual starting dose 500 mg Usual treatment dose 1500 mg Side effects: GI disturbances nb: lactic acidosis Insulin sensitizing agents

45 Metformin - side effects Gastro-intestinal Metallic taste in the mouth Anorexia Nausea Abdominal discomfort (bloating) Diarrhea Lowers serum vitamin B12 concentrations but does not cause anemia At large doses diarrhea is the most common side effect stepping back a dose will frequently improve (decrease) side effects and increase tolerability ~ 5% of patients are intolerant Insulin sensitizing agents

46 Lactic acidosis Rare Fatal in ~ 50% of cases ~ 9 / 100,000 person yrs (compared with 50 / 100,000 persons yrs for phenformin) Risk factors for developing LA = contra-indications Renal insufficiency (serum creatinine > 1.5 mg/dl) Concurrent liver disease or alcohol abuse Heart failure History of lactic acidosis Severe infection with decrease tissue perfusion Hypoxic states Serious acute illness Hemodynamic instability Age > 80 yrs Insulin sensitizing agents

47 Cimetidine may lower renal clearance of metformin Iodinated contrast?????? Package insert say discontinue for 48 hours after parenterally administered iodinated contrast Contrast-induced acute renal failure Insulin sensitizing agents

48 Insulin sensitizing agents 500 mg po qd x 14 days then if tolerating medication well increase to 500 mg po bid x 14 days then if tolerating medication well increase to 1500 mg daily LFT s every 6 to 12 months (?)

49 Questions????

50 Sex Steroids A steroid is a terpenoid (a large and diverse class of naturally occurring organic chemicals) lipid characterized by a carbon skeleton with four fused rings, generally arranged in a fashion. Steroids can vary by the functional groups attached to these rings and the oxidation state of the rings. Hundreds of distinct steroids are found in plants, animals, and fungi. All steroids are biosynthetically derived either from the sterol lanosterol (animals and fungi) or the sterol cycloartenol (plants). Both sterols are derived from the cyclization of the triterpene squalene

51 Steroids Animal steroids Insect steroids (ecdysteroids) Vertebrate steroids Sex steroids Corticosteroids Anabolic steroids Cholesterol Plant steroids Phytosteroids Brassinosteroids Fungus steroids Ergosterols

52 Steroids Steroid hormones Sex steroids that produce sex differences and support reproduction: androgens estrogens progestagens Corticosteroids Glucocorticoids regulate many aspects of metabolism Mineralocorticoids maintain blood volume and control renal function Anabolic steroids interact with androgen receptors to increase muscle and bone synthesis. natural synthetic

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55 cholesterol a H A desmolase B 4 6 P450 SCC H 3 B ol HSD C 3 B ol HSD H H Pregnenolone 17H Preg DHEA H H H 21 H ase Progesterone H 17H P4 A dione Testosterone H H 11B H ase Deoxy corticosterone H H Desoxy cortisol H H H H Estrone H Estradiol 17B HSD 18 H ase Corticosterone H Cortisol Aromatase H = C C = Aldosterone

56 Steroidogenesis The ovaries lack: 21 alpha hydroxylase 11 B hydroxylase

57 Estrogens estrane 18 carbons Androgens androstane 19 carbons Progestagens Pregnane 21 carbons Sex Steroids

58 What is. An estrogen? anabolic steroid, that results in development of female secondary sexual characteristics, feminization and supports reproduction. Primarily produced in the ovary An androgen? An anabolic steroid, that results in the development of male secondary sexual characteristics, masculization and aids in the development of male gametes (sperm), primarily produced in the testis A progestagen? Steroid hormone, aids in the preparation of the reproductive tract and gametes for fertilization, implantation and maintenance of the uterine environment during gestation

59 Progestagens Progestagens Natural progesterone Synthetic progestins

60 Production vary mid-luteal corpus luteum 50 mg/day Adrenal glands Syncytio-trophoblast term placenta 250 mg/day Transport 95-98% bound Albumin ~ 79% Cortisol binding globulin (CBG) ~ 18% Sex hormone binding globulin (SHBG) ~ 1% Metabolism 50% hepatic 50% extra-hepatic Reduction and hydroxylation Progesterone

61 Progesterone Mechanism of action Progesterone receptors hpr - A hpr B Non-genomic (effects that do not obey the properties of classical receptor steroid complex interaction with the cellular genome) eg binds to sperm surface receptors rapid uptake of calcium, facilitating the acrosome reaction

62 Progestagens H H Testosterone 19 nor testosterone

63 H Progestagens H. C CH Testosterone Ethisterone H. C CH Norethindrone

64 Progestagens Norethindrone Drospirenone

65 Progestagens Progesterone Provera Megace

66 By progestin potency Name Progestin activity Androgen activity medroxyprogesterone acetate megestrol acetate norethindrone 1 1 norethindrone acetate norgestimate norelgestromin ethynodiol diacetate drospirenone dl-norgestrel levonorgestrel desogestrel gestodene Progestins By androgen potency Name Progestin activity Androgen activity medroxyprogesterone acetate megestrol acetate drospirenone ethynodiol diacetate norethindrone 1 1 norethindrone acetate norgestimate norelgestromin desogestrel dl-norgestrel levonorgestrel gestodene

67 Progestagens generic trade dose 1 dose 2 dose 3 dose 4 route medroxyprogesterone acetate Provera 2.5 mg 5 mg 10 mg 0 P medroxyprogesterone acetate Cycrin 2.5 mg 5 mg 10 mg 0 P medroxyprogesterone acetate Amen 10 mg P medroxyprogesterone acetate DepoProvera 150 mg IM norethindrone acetate Aygestin 5 mg P norethindrone acetate Norlutate 5 mg P norethindrone Micronor 0.35 mg P norgestrel vrette mg P micronized progesterone Prometrium 100 mg 200 mg 0 0 P / vaginal micronized progesterone Endometrin 100 mg P / vaginal micronized progesterone gel Prochieve 45 mg (4%) 90 mg (8%) 0 0 vaginal micronized progesterone gel Crinone 45 mg (4%) 90 mg (8%) 0 0 vaginal progesterone in oil 50 mg /ml 0 0 0

68 Indications Endometrial maturation - withdrawal bleed Contraception Luteal support Endometriosis Endometrial hyperplasia / cancer Pelvic pain Progestagens

69 Progestagens Atypical endometrial hyperplasia Megace 40 mg po bid x 3 months (?) Withdrawal bleed Provera 10mg po qd x 10 d Prometrium 300mg qd x 10 days Endometriosis Provera 10mg po bid x 6 months (?) Luteal support Prometrium 300mg po or vaginally tid Progesterone in oil 50mg IM

70 Estrogens Parent compound: estrane 18 carbons Notable features Aromatic ring A Phenolic hydroxyl group at C3 position xygen atom (hydroxyl or ketone group) at position C17

71 Estrogens

72 Production Estradiol Follicular 0.09 mg/day Luteal 0.25 mg/day Estrone Follicular 0.11 mg/day Luteal 0.26 mg/day Transport 98% bound Sex hormone binding globulin (SHBG) ~ 70% Albumin ~ 28% Metabolism Hepatic mostly to glucuronosides 50-80% in the urine, up to 20% in the feces inactive, water soluble compounds Catechol estrogens probably not clinically significant Estrogen

73 Estrogens Estrone: a contributor to the total body estrogen effect Androstenedione 3000 ug/24 hr Testosterone 250 ug/24 hr 1.5% 0.15% Estrone 45 ug/24 hr Estradiol ug/24 hr Peripheral conversion

74 rally active Conjugated equine estrogens (Premarin) Ten biologically active estrogens Pregnant mares urine (Pre mar in) Synthetic conjugated estrogens (Cenestin) Mixture of nine synthetically derived estrogenic compounds Made from yam and soy sources Esterified estrogens (Estratab) Estrone and equilin esters Micronized estradiol (Estrace) 17 B estradiol Ethinyl estradiol (Estinyl) Estradiol with an ethinyl group Estrogens

75 Vaginal creams Conjugated equine estrogens (Premarin) Micronized estradiol (Estrace) Vaginal Rings Estradiol Vaginal tablet Estradiol Estrogens

76 Transdermal Estradiol IM preparations Estradiol in cottonseed oil or castor oil Estrogens

77 Relative estrogen potencies Estrogens Estrogen FSH Liver proteins Bone density Conjugated estrogens 1.0 mg mg mg Micronized estradiol 1.0 mg 1.0 mg 1.0 mg Estropipate 1.0 mg 1.25 mg 1.25 mg Ethinyl estradiol 5.0 ug 2-10ug 5.0ug Estradiol valerate 1.0 mg Esterified estrogens mg Transdermal estrogens 50 ug

78 Estrogens rally active Conjugated Estrogens (Premarin, Cenestin) 0.3, 0.625, 0.9, 1.25 Estropipate (rtho Est, gen) 0.75, 1.5 Esterified Estrogens (Estratab) 0.625, 1.25 Estradiol (Estrace) 0.5, 1.0, 2.0 Ethinyl Estradiol (Estinyl - used in CPs) 20ug, 50ug Transdermal Estradiol (Estraderm) twice a week.05, 0.1 Estradiol (Climera) once a week.05,.075,.1 Estradiol (Vivelle) twice a week ,.05,.075,.1 Estradiol (Fempatch) once a week.025 Estradiol (Esclim) twice a week.025,.0375,.05,.075,.1 Estradiol (Alora) twice a week.05,.075,.1 Vaginal Estradiol (Estring) once a month 2 mg (7.5 ug / 24 hr) Estradiol acetate (Femring) once a month 12.4 mg (0.05 mg/24 hr) once a month 24.8 mg (0.10 mg/24 hr) Estradiol (Vagifem) once a day 25 ug

79 Indications Menopausal syndrome steoporosis Vaginal atrophy Endometrial development Breast development Estrogens

80 Estrogen Prescribing estrogen Use the lowest effective dose Limit exposure (?) Staff recommendations

81 generic trade dose 1 dose 2 dose 3 dose 4 dose 5 route estradiol cypionate Depo-Estradiol 1 mg / ml IM estradiol valerate Delestrogen 10 mg/ml 20 mg/ml 40 mg/ml IM piperazine estrone sulfate (estropipate) gen P estinyl estradiol Estinyl P synthetic conjugated estrogens Cenestin P conjugated equine estrogens Premarin P micronized 17 B estradiol Estrace P esterified estrogens Menest P esterified estrogens Estratab P 17 B estradiol Climara transdermal estradiol transdermal Vivelle mg mg 0.05 mg mg 0.1 mg transdermal 17 B estradiol Alora transdermal 17 B estradiol Estraderm transdermal estradiol acetate vaginal ring Femring 12.4 (0.05 mg/24 hr) 24.8 (0.1 mg/24 hrs) 0 0 vaginal conjugated equine estrogen cream Premarin Cream mg / gram 0 0 vaginal estradiol cream Estrace Cream 0.1 mg / gram vaginal estradiol vaginal ring Estring 2 mg (7.5 ug/24 hr) 0 0 vaginal