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. To be able to review the physiology of normal menstrual cycle 2. To list the different sex hormones, know their biosynthesis (chemical compositions), mechanism of action, pharmacokinetic properties, physiologic and metabolic effects 3. To describe clinical/therapeutic applications of these hormones 4. To list side effects and/or adverse reactions to these drugs

Outline I. Physiology of Reproductive Hormones II. 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. Physiology of Reproductive Hormones II. 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: carbon series – PROGESTINS (pregnane nucleus) carbon series - ANDROGENS (androstane nucleus) carbon series - ESTROGENS (estrane nucleus) What regulates the synthesis of sex hormones? What regulates the synthesis of sex hormones?

Hypothalamic-Pituitary-Gonadal Axis

Hypothalamic-Pituitary-Reproductive Axis: TWO CELL- SYSTEMS (Androstenedione) (Testosterone)

Hypothalamic-Pituitary-Reproductive Axis: TWO CELL- SYSTEMS LHLHFSHFSH MALE L eydig S ertoli Te stosterone synthesis Increases production of ABP S S permatogenesis FEMALEThecaGranulosa Androstenedione synthesis Increases 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

 Major natural estrogens in human Actions mediated by ESTROGEN RECEPTORS (alpha and beta) which are ligand-regulated transcription factors The Estrogens

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

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 Hydroxyprogesterone acetate Medroxyprogesterone acetate Megestrol Dimethisterone * Most closely related to progesterone Desogestrel Gestodene Norgestimate ** claimed to have lower androgenic activity than older synthetic progestins 21 carbon compounds 19-nor, 13 ethyl compounds

 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 Promote endometrial development during luteal phase  Decreases amount of cervical mucus and increases its viscosity  Increases basal body temperature

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 CO 2 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: DIAGNOSTICDIAGNOSTIC 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 dose- related DOSE OF ESTROGEN – a critical issue in selecting an oral contraceptive

COMBINATION ORAL CONTRACEPTIVES (COCS) – PROGESTIN COMPONENT 42

The Pharmacology of the Progestin Component of COCs 2 major types of synthetic progestins 1. Derivatives of 19 nortestosterone 2. Derivatives of 17 α acetoxyprogesterone

The Pharmacology of the Progestin Component of COCs 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 ETHISTERONE TESTOSTERONE NORETHINDRONE

The Pharmacology of the Progestin Component of COCs ESTRANES Norethindrone Norethynodrel Norethindrone acetate Ethynodiol acetate GONANES Levonorgestrel Norgestimate* Gestodene* Desogestrel* * With greater progestational activity 19 NORTESTOSTERONE

The Pharmacology of the Progestin Component of COCs Norethindrone family (most are converted to the parent compound, norethindrone) Norethindrone Norethynodrel Norethindrone acetate Ethynodiol diacetate Lynestrenol Norgestrel

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

C21 progestins PREGNANES Structurally related to progesterone Medroxyprogesterone acetate and megestrol acetate Marketed for noncontraceptive usage 17 α ACETOXYPROGESTERONE

COCs “ Current formulations of COCs are made from SYNTHETIC steroids and contain no natural estrogens or progestins.”

synthetic progestins Ethinyl estradiol

Definitions Low Dose Oral Contraceptives – products with <50ug of EE 1 st generation COCs – products with > 50ug of EE 2 nd generation COCs – products with levonorgestrel,norgestimate, and other members of the norethindrone family and <50ug EE 3 rd 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)

Suppress ovulation Change endometrium making implantation less likely Thicken cervical mucus (preventing sperm penetration) Reduce sperm transport in upper genital tract (fallopian tubes) COCs Mechanism of Action Progestin suppresses LH secretion Estrogen suppresses FSH secretion ProgestinProgestin the effect of a progestational agent will always take precedence over estrogen

Estrogen in the COCs ESTROGEN serves 2 other purposes: 1) it provides STABILITY to the endometrium so that irregular shedding and unwanted breakthrough bleeding can be minimized 2) 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 1 st 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

COCs: Contraceptive Benefits 68 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 Incidental benefits 2. Benefits to treat and manage problem and disorders

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 Incidental benefits 2. Benefits to treat and manage problem and disorders Dysmennorhea Endometriosis Replacement therapy in ovarian dysfunction DUB Postmenopausal symptoms

COCs: Absolute Contraindications 1. Thrombophlebitis, thromboembolic disorders, cerebrovascular disease, coronary occlusion or past history of these conditions 2. Severe hypercholesterolemia or hypertriglyceridemia 3. Untreated hypertension 4. Smokers over the age of Known or suspected breast cancer 6. Markedly impaired liver function 7. Undiagnosed abnormal vaginal bleeding 8. Known or suspected pregnancy

COCs: Relative Contraindications 1. Systemic lupus erythematosus 2. Sickle cell disease 3. Gestational diabetes mellitus 4. Diabetes mellitus 5. Hyperlipidemia 6. Controlled hypertension 7. Smoking 8. Migraine headaches 9. Seizure disorder

COCs: Relative Contraindications 10. Hepatic disease 11. Obstructive jaundice in pregnancy 12. Gallbladder disease 13. Mitral valve prolapse 14. Uterine leiomyomas 15. 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

COCs: Clinical Problems 79 Breakthrough bleeding Amenorrhea Weight gain Ovarian cysts

COCs: Clinical problems BREAKTHROUGH BLEEDING 1. Irregular bleeding in the first few months after starting oral contraception 2. Unexpected bleeding after many months of use *There is NO evidence that the onset of bleeding is associated with decreased efficacy; no matter what oral contraceptive formulation is used, even the lowest dose products

COCs: Clinical problems BREAKTHROUGH BLEEDING Most frequently encountered occurs in the first few months of use Higher in women who smoke Best managed by ENCOURAGEMENT & REASSURANCE Disappears by the 3 rd cycle Represents tissue breakdown as the endometrium adjusts from its usual thick state to the relatively thin state allowed by hormones in OC

COCs: Clinical problems BREAKTHROUGH BLEEDING BB after many months of use is a consequence of progestin-induced decidualization Endometrium and blood vessels within the endometrium tend to be fragile and prone to breakdwon and asynchronous bleeding

COCs: Clinical problems BREAKTHROUGH BLEEDING 2 factors associated with BB: 1. Inconsistency of pill taking- more important and hasa greater effect in later cycles 2. Smoking – exerts a general effect at any time REINFORCEMENT OF CONSISTENT PILL- TAKING can help minimize BB

COCs: Clinical problems BREAKTHROUGH BLEEDING If bleeding occurs before the end of the cycle – stop the pills wait 7 days start a new cycle If BB is prolonged or is aggravating to the patient -- Conjugated estrogen 1.25mg Estradiol 2mg 7 days

COCs: Clinical problems BREAKTHROUGH BLEEDING Taking of 2-3 pills is NOT effective The PROGESTIN component will always dominate – doubling the pills → double the progestational impact → double the decidualizing and atrophic effect on the endometrium and destabilizing effect on endometrial blood vessels ADD ESTROGEN ( do not add progestin)

COCs: Clinical Problems AMENORRHEA With low dose pills, the estrogen content is not sufficient to stimulate endometrial growth Progestational effect dominates to such a degree that a shallow atrophic endometrium is produced, lacking sufficient tissue to yield withdrawal bleeding → AMENORRHEA There is no harmful permanent consequence of amenorrhea while on OC ANXIETY in both patient and clinician -- major problem

COCs: Clinical Problems AMENORRHEA Patient is anxious because of uncertainty regarding pregnancy Clinician is anxious because of medicolegal concerns stemming from old studies which indicated increased risk of congenital abnormalities Recent reviews showed that there is NO ASSOCIATION between oral contraception and increased risk for congenital malformation and there is NO increased risk of having abnormal children

COCs: Drugs that Affect Efficacy OCs potentiate the action of Diazepam Chlordiazepoxide Tricyclic antidepressants Theophylline LOWER doses of the above agents in OC users OCs alter clearance rates of Paracetamol and ASA LARGER doses may be required in OC users

Progestin-Only Pills (POPs) 89

POPs: Mechanisms of Action Suppress ovulation (not consistently suppressed) Change endometrium making implantation less likely Thicken cervical mucus (preventing sperm penetration) ? Reduce sperm transport in upper genital tract (fallopian tubes)

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: Efficacy Effective when taken at the same time every day (0.05–5 pregnancies per 100 women during the first year of use)

POPs: Contraceptive Benefits 93 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

POPs: Noncontraceptive Benefits 94 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

POPs: Problems Irregular menstrual bleeding – major reason why women discontinue POPs More functional ovarian cysts Levonorgestrel associated with acne

POPs: Pill taking Minipill should be started on the first day of menses Back-up method must be used for the 1 st seven days because some women may ovulate as early as 7-9 days after menses Pill intake should be keyed to a daily event to ensure regular administration at the same time of the day Missed pills – take missed pill ASAP, back-up method should be used until resumed for at least 2 days If more than 3hrs late – back-up method for 2 days

POPs: Clinical Decisions 2 situations in which excellent efficacy is achieved: 1. 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 2. 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

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-pituitary- gonadal axis, impair ovum transport Adverse effects nausea and vomiting, headache, dizziness, breast tenderness, abdominal and leg cramps Post-coital contraception

Schedules for Use of Post-coital Contraceptives Conjugated Estrogens 10mg TID for 5 days Ethinyl Estradiol2.5mg BID for 5 days Mifepristone600mg once (with Misoprostol 400 ucg once) L-Norgestrel0.75mg BID for 1 day Norgestrel EE 0.5mg 2 tab and 0.05mg 2 tabs in 12 hours