Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Drugs for Reproductive Endocrinology: Focus on OCP therapeutics Ma. Stephanie Fay S. Cagayan, MD, FPOGS General Objective To acquire an understanding of the action of the different sex hormones and other hormones utilized in the pharmacology of hormonal contraception Reference: Chapter 40, Basic and Clinical Pharmacology 1th edition (Katzung) Specific Objectives 1. 2. 3. 4. To be able to review the physiology of normal menstrual cycle To list the different sex hormones, know their biosynthesis (chemical compositions), mechanism of action, pharmacokinetic properties, physiologic and metabolic effects To describe clinical/therapeutic applications of these hormones To list side effects and/or adverse reactions to these drugs Outline I. II. Physiology of Reproductive Hormones Female Gonadal Hormones Estrogen and Progesterone ORAL CONTRACEPTION Different Hormones in Reproductive Endocrinology Biosynthesis (chemical compositions) Mechanism of action Pharmacokinetic properties Physiologic and Metabolic effects Clinical / Therapeutic Application Adverse Effects Outline I. II. Physiology of Reproductive Hormones Female Gonadal Hormones Estrogen and Progesterone ORAL CONTRACEPTION Sex hormones = gonadal hormones estrogens progestins androgens Gonadotropins LH FSH GnRH Gonadal Hormones SYNTHESIS OF SEX STEROIDS Gonadal Hormones SEX HORMONES: 1. 21 carbon series – PROGESTINS (pregnane nucleus) 2. 19 carbon series - ANDROGENS (androstane nucleus) 3. 18 carbon series - ESTROGENS (estrane nucleus) What regulates the synthesis of sex hormones? Hypothalamic-Pituitary-Gonadal Axis Hypothalamic-Pituitary-Reproductive Axis: TWO CELLSYSTEMS (Testosterone) (Androstenedione) Hypothalamic-Pituitary-Reproductive Axis: TWO CELLSYSTEMS MALE LH FSH Leydig Sertoli Testosterone Increases production of ABP synthesis FEMALE Theca Spermatogenesis Granulosa Androstenedione Increases synthesis aromatase activity Prerequisites of Normal Menstruation an intact HPO axis estrogen-induced proliferative endometrium ovulation at midcycle progesterone-induced secretory endometrium if pregnancy does not occur, the hormones decline, and withdrawal bleeding occurs CH 3 OH H H H CH3 HO ESTRADIOL O H H H CH3 OH HO H ESTRONE H OH H HO ESTRIOL The Estrogens Major natural estrogens in human Actions mediated by ESTROGEN RECEPTORS (alpha and beta) which are ligand-regulated transcription factors Some synthetic estrogens The Estrogens Biosynthesis (chemical compositions) Mechanism of action Pharmacokinetic properties Physiologic and Metabolic effects Clinical / Therapeutic Application Adverse Effects Steroid Hormone and its Receptor Estrogen Receptor Actions mediated by ESTROGEN RECEPTORS (alpha and beta) which are ligand-regulated transcription factors The Estrogens: Pharmacokinetics Estradiol (E2) binds STRONGLY to α globulin (SHBG) LOWER affinity to albumin E2 (liver) → Estrone (E1) and Estriol(E3) → hydroxylated derivatives and conjugated metabolites Orally administered estrogens have HIGH ratio of hepatic to peripheral effects → responsible for the increased clotting factors and increased renin substrate Clinical / Therapeutic Application Primary hypogonadism Hormonal contraception Post-menopausal hormonal therapy The Estrogens Biosynthesis (chemical compositions) Mechanism of action Pharmacokinetic properties Physiologic and Metabolic effects Clinical / Therapeutic Application Adverse Effects Adverse Effects Uterine bleeding Endometrial cancer Other effects: nausea, breast tenderness The Natural Progestins: Progesterone The most important progestin in human Serves as a precursor to the estrogens, androgens and adrenocortical steroids Synthesized in the ovary, testis and adrenal from circulating cholesterol; large amounts are also synthesized and released by the placenta during pregnancy The Synthetic Progestins 21 carbon compounds Hydroxyprogesterone acetate Medroxyprogesterone acetate Megestrol Dimethisterone * Most closely related to progesterone 19-nor, 13 ethyl compounds Desogestrel Gestodene Norgestimate ** claimed to have lower androgenic activity than older synthetic progestins The Progestins Actions are mediated by progesterone receptors (A and B isoforms) which are ligand-activated transcription factors The concentration of progesterone receptors is dependent on previous estrogen action The Progestins Biosynthesis (chemical compositions) Mechanism of action Pharmacokinetic properties Physiologic and Metabolic effects Clinical / Therapeutic Application Adverse Effects The Progestins: Pharmacokinetics Progesterone is rapidly absorbed following administration by any route t ½ is 5minutes Almost completely metabolized in one passage through the liver In the liver, it is metabolized to pregnanediol and conjugated with glucuronic acid It is excreted into the urine as pregnanediol glucuronide The Progestins Biosynthesis (chemical compositions) Mechanism of action Pharmacokinetic properties Physiologic and Metabolic effects Clinical / Therapeutic Application Adverse Effects Physiologic Effects Decreases amount of cervical mucus and increases its viscosity Promote endometrial development during luteal phase Increases basal body temperature The Physiologic Effect of Progestins Progesterone ATTENUATES estrogen action on the endometrium in 3 ways: By reducing the rate of synthesis of ER molecules By increasing the rate of enzymatic inactivation By effecting estrogen inactivation through sulfuration The Physiologic Effect of Progestins Physiologic Effects: Progesterone Has little effect on protein metabolism Has more marked effect on carbohydrate metabolism: progesterone INCREASES basal insulin levels and the insulin response to glucose Antagonize actions of aldosterone Physiologic Effects: Progesterone Increases body temperature Has depressant and hypnotic effects on the brain Increases ventilatory response to CO2 Stimulate growth and development of breasts during pregnancy Its effects on the uterus are essential for maintenance of pregnancy Clinical Application THERAPEUTIC APPLICATION: Hormonal contraception Hormonal replacement therapy Endometriosis Clinical Application: D I A G N O S T I C A test of estrogen secretion: Progesterone challenge test MPA 10mg/d for 5 days - when endometrium has been stimulated by estrogens (+) withdrawal bleeding Adverse Effects Headache Dizziness Bloating Weight gain Reversible reduction of glucose tolerance Hormonal contraception in women Combination of progestins and estrogens – Combination oral contraceptives (COCs) Progestin only pills (POPs) The Pharmacology of the Estrogen Component of COCs E2 is the most potent natural estrogen --inactive orally E2 + ethinyl group at the 17 position = Ethinyl Estradiol --orally active The Pharmacology of the Estrogen Component of COCs Metabolism of EE VARIES SIGNIFICANTLY from individual to individual, and from one population to another ESTROGEN CONTENT of the pill is of major clinical importance ---- THROMBOSIS is doserelated DOSE OF ESTROGEN – a critical issue in selecting an oral contraceptive 42 COMBINATION ORAL CONTRACEPTIVES (COCS) – PROGESTIN COMPONENT The Pharmacology of the Progestin Component of COCs 2 major types of synthetic progestins 1. Derivatives of 19 nortestosterone 2. Derivatives of 17α acetoxyprogesterone The Pharmacology of the Progestin Component of COCs TESTOSTERONE ETHISTERONE NORETHINDRONE Removal of 19-carbon from ethisterone formed NORETHINDRONE → changed major hormonal effect from an androgen to progestational agent → 19 nortestosterone - all progestational agents have some degree of androgenic activity The Pharmacology of the Progestin Component of COCs 19 NORTESTOSTERONE GONANES ESTRANES Levonorgestrel Norethindrone Norgestimate* Norethynodrel Gestodene* Norethindrone acetate Desogestrel* Ethynodiol acetate * With greater progestational activity The Pharmacology of the Progestin Component of COCs Other progestins Levonorgestrel is the active isomer of norgestrel New progestins • Desogestrel, gestodene, norgestimate are derivatives of levonorgestrel Reduced androgenicity (increased sex hormone binding globulin, decreased free testosterone) Drospirenone – analogue of spironolactone, has affinity for mineralocorticoid receptor and antimineralocorticoid effect (Yasmin) The Pharmacology of the Progestin Component of COCs 17 α ACETOXYPROGESTERONE C21 progestins PREGNANES Structurally related to progesterone Medroxyprogesterone acetate and megestrol acetate Marketed for noncontraceptive usage COCs “ Current formulations of COCs are made from SYNTHETIC steroids and contain no natural estrogens or progestins.” Ethinyl estradiol synthetic progestins Definitions Low Dose Oral Contraceptives – products with <50ug of EE 1st generation COCs – products with > 50ug of EE 2nd generation COCs – products with levonorgestrel,norgestimate, and other members of the norethindrone family and <50ug EE 3rd generation COCs – products with desogestrel or gestodene and <50ug of EE Types of COCs Usually containing ethinyl estradiol and norethindrone Administered with interruption (21 days on, 7 days off) Monophasic: All 21 active pills contain same amount of Estrogen/Progestin (E/P) Biphasic: 21 active pills contain 2 different E/P combinations (e.g., 10/11) Triphasic: 21 active pills contain 3 different E/P combinations (e.g., 6/5/10) COCs Mechanism of Action Estrogen suppresses FSH secretion Suppress ovulation Progestin suppresses LH secretion Reduce sperm transport in upper genital tract (fallopian tubes) Change endometrium making implantation less likely Thicken cervical mucus (preventing sperm penetration) P r o g e s t i n the effect of a progestational agent will always take precedence over estrogen Estrogen in the COCs ESTROGEN serves 2 other purposes: 1) 2) it provides STABILITY to the endometrium so that irregular shedding and unwanted breakthrough bleeding can be minimized It potentiates the action of the progestational agents -allowed reduction of the progestational dose in the pill increasing the concentration of intracellular progestational receptors. * Therefore a minimal pharmacologic level of estrogen is necessary to maintain the efficacy of the COCs Oral Contraceptive Pills COCs: Efficacy Perfect use failure rate: 0.1% Typical use failure rate: 7.6% Pregnancies usually occur because initiation of the next cycle is delayed Strict adherence to 7-pill free days is critical to obtain contraception If with vomiting & diarrhea → back-up method for 7days→ put pill in the vagina COCS: METABOLIC EFFECTS COCs: Metabolic Effects Thrombosis Thrombosis can be divided into 2 major categories: 1. Venous thromboembolism deep vein thrombosis pulmonary embolism 2. Arterial thrombosis myocardial infarction stroke COCs: Metabolic Effects Thrombosis Pharmacologic estrogen increases the production of clotting factors (II, VII, IX, X) Progestins have no significant impact on clotting factors Past users of oral contraceptives DO NOT have an increases incidence of cardiovascular disease Hypertension is a very important additive risk factor for stroke in OC users COCs: Metabolic Effects Thrombosis All low dose OCs, regardless of progestin type, have an increased risk of VTE, concentrated in the 1st 2 years of use Recent studies reinforce the belief that the risks of arterial and venous thrombosis are a consequence of the ESTROGEN component of COCs Smoking has a lesser effect on the risk of venous thrombosis compared with arterial thrombosis Smoking and estrogen have an additive effect on the risk of arterial thrombosis COCs: Metabolic Effects Thrombosis Low dose OCs DO NOT increase the risk of MI or stroke in healthy, non-smoking women, regardless of age Almost all MI and strokes in OC users occur in users of HIGH dose products or users WITH CARDIOVASCULAR RISK FACTORS Cardiac deaths occurred in only in women who smoked >15 cigarettes per day COCs: Metabolic Effects Thrombosis New studies emphasize the importance of good patient screening - arterial thrombosis is limited to older women who smoke or have cardiovascular risk factors - no increase in mortality due to MI or stroke in healthy,non-smoking women If a patient has a family history of idiopathic thromboembolism, an evaluation to search for an underlying abnormality in the coagulation system is warranted COCs: Metabolic Effects - Conclusion “ LOW DOSE oral contraceptives are VERY SAFE for healthy young women.” COCs : Carbohydrate Metabolism Older high dose OCs – (+) impaired glucose tolerance Insulin sensitivity is affected mainly by the PROGESTIN component of the pill Glucose intolerance is dose-related Insulin and glucose changes with low dose monophasic and multiphasic OCs are so minimal and clinically insignificant COCs : Carbohydrate Metabolism “ It can be stated definitely that oral contraceptive use DOES NOT produce an increase in diabetes mellitus.” COCs: The Risk of Breast Cancer Current and recent (1-4years) use of OCs may be associated with 20% increased risk of early (<35) premenopausal breast cancer, essentially limited to localized and a very small increase in the number of actual cases May be due to: 1.) detection/surveillance bias 2.) accelerated growth of already present malignancies COCs: The Risk of Breast Cancer NO EFFECT of past use or duration of OC use (up to 15 years of continuous use) NO INCREASED RISK on use of high dose OCs Previous use may be associated with a REDUCED RISK of metastatic cancer LATER in life, and REDUCED RISK of postmenopausal breast cancer NO INCREASED RISK in women with positive family history for breast cancer/women with benign breast disease 68 COCs: Contraceptive Benefits Most important use is for ORAL CONTRACEPTION Pelvic examination not required to initiate use Do not interfere with intercourse Few side effects Convenient and easy to use Client can stop use Can be provided by trained non-medical staff COCs: Noncontraceptive Benefits 1. 2. Incidental benefits Benefits to treat and manage problem and disorders 69 COCs: Incidental Benefits LESS ENDOMETRIAL CANCER Use for 12 months reduces the risk by 50% Greatest protective effect if use for >3 years LESS OVARIAN CANCER Risk is reduced by 40% (3 years) to 80% (>10 years of use) COCs: Incidental Benefits Fewer ectopic pregnancies More regular menses – less flow, dysmenorrhea, anemia Less salpingitis Increased bone density Possibly less benign breast disease Possibly fewer ovarian cysts COCs: Noncontraceptive Benefits 1. 2. Incidental benefits Benefits to treat and manage problem and disorders Dysmennorhea Endometriosis Replacement therapy in ovarian dysfunction DUB Postmenopausal symptoms 72 COCs: Absolute Contraindications 1. 2. 3. 4. 5. 6. 7. 8. Thrombophlebitis, thromboembolic disorders, cerebrovascular disease, coronary occlusion or past history of these conditions Severe hypercholesterolemia or hypertriglyceridemia Untreated hypertension Smokers over the age of 35 Known or suspected breast cancer Markedly impaired liver function Undiagnosed abnormal vaginal bleeding Known or suspected pregnancy COCs: Relative Contraindications 1. 2. 3. 4. 5. 6. 7. 8. 9. Systemic lupus erythematosus Sickle cell disease Gestational diabetes mellitus Diabetes mellitus Hyperlipidemia Controlled hypertension Smoking Migraine headaches Seizure disorder COCs: Relative Contraindications 10. 11. 12. 13. 14. 15. Hepatic disease Obstructive jaundice in pregnancy Gallbladder disease Mitral valve prolapse Uterine leiomyomas Elective surgery Clinical Decisions: Surveillance Can be prescribed without a clinical breast and pelvic examination Patients need be seen only every 12months Perform yearly breast and pelvic examination on follow up Reassess new users within 1-2months “ COCs are safer than most people think. ” FEAR OF SIDE EFFECTS: most common reason why patients discontinue oral contraception Clinical Decisions: Surveillance Laboratory surveillance should be used only when indicated The ff patients should be monitored with blood screening tests for glucose, lipids and lipoproteins: Young women, at least once Women >35 y/o Women with strong family history of heart disease, DM,HPN Women with GDM Obese women Diabetic women COCs: Choice of Pill The therapeutic principle remains: “ Utilize the formulations that give effective contraception and the greatest margin of safety.” Current data support that there is GREATER safety with low dose preparations There is LITTLE difference between the low dose monophasics and the multiphasics 89 Progestin-Only Pills (POPs) POPs: Mechanisms of Action Suppress ovulation (not consistently suppressed) ? Reduce sperm transport in upper genital tract (fallopian tubes) Change endometrium making implantation less likely Thicken cervical mucus (preventing sperm penetration) POPs: Mechanisms of Action Contains a small dose of a progestational agent Must be taken daily in a continuous fashion Must be taken every day of the SAME TIME Change in cervical mucus - requires 2-4hours to take effect - impermeability diminishes 22 hours after administration - by 24hours sperm penetration is essentially unimpaired POPs: Contraceptive Benefits Pelvic examination not required prior to use Do not interfere with intercourse Do not affect breastfeeding Immediate return of fertility when stopped Few side effects Convenient and easy-to-use Client can stop use Can be provided by trained nonmedical staff Contain no estrogen 93 POPs: Noncontraceptive Benefits May decrease menstrual cramps May decrease menstrual bleeding May improve anemia Protect against endometrial cancer Decrease benign breast disease Decrease ectopic pregnancy Protect against some causes of PID 94 POPs: Clinical Decisions 1. 2. 2 situations in which excellent efficacy is achieved: Lactating women - no evidence of any adverse effect on breastfeeding - women breastfeed longer and add supplementary feeding at a later time - can be started IMMEDIATELY after delivery Women age over 40 Postcoital contraception Types: estrogen (ethinyl estradiol) + progestin (norgestrel); estrogen alone progestin alone High doses but for a few days Effectiveness: 90-98% if taken within 72 hours of unprotected intercourse Post-coital contraception Mechanism of action • If fertilization has occurred: prevents • implantation, promotes menstrual bleeding If fertilization has not occurred: decrease the amount and increase the viscosity of cervical mucus, suppress the hypothalamic-pituitarygonadal axis, impair ovum transport Adverse effects • nausea and vomiting, headache, dizziness, breast tenderness, abdominal and leg cramps Schedules for Use of Post-coital Contraceptives Conjugated Estrogens 10mg TID for 5 days Ethinyl Estradiol 2.5mg BID for 5 days Mifepristone L-Norgestrel 600mg once (with Misoprostol 400 ucg once) 0.75mg BID for 1 day Norgestrel EE 0.5mg 2 tab and 0.05mg 2 tabs in 12 hours