Understanding

Alexandra Hall MD University of Wisconsin, Stout ACHA 2013 Disclosures • I will discuss off-label use of . • I have no financial conflicts of interest. Overview • Mechanisms of Action • Risks & benefits, based on & physiologic effects • Safe prescribing, weighing the options Abbreviations

• CHC = Combined Hormonal Contraceptive • + Progestin • Pills, Patch, & Ring • BC = • OC = Oral Contraceptive (COC=Combined Oral Contraceptive) • POP = Progestin-Only Pills, a.k.a. Mini-Pills • LNG-IUS = Intrauterine System (Mirena IUD) • DMPA = Depot-medroxyprogesterone acetate (Depo-Provera) • EE = Ethinyl • SHBG = sex binding globulin • MEC = Medical Eligibility Criteria U.S. MEC www.cdc.gov/reproductivehealth/UnintendedPregnancy/USMEC.htm Resources • Hatcher et al., Contraceptive Technology • Dickey, Managing Contraceptive Pill / Drug Patients • Speroff & Fritz, Clinical Gynecologic Endocrinology and • Speroff & Darney, A Clinical Guide for Contraception • Association of Reproductive Health Professionals www.arhp.org • Free webinars • Free online resources • Free patient resources • Members get free subscription to journal Contraception LET’S GET STARTED! Case

Astara believes strongly in using only natural products and doesn’t want to use anything synthetic. She wonders if there is an all-natural hormonal contraceptive available to her. What do you tell her?

a. The in OC’s are identical to the hormones her body normally makes. b. The hormones in a new pill named Natazia are bioidentical to natural hormones. c. The estrogen component of CHC is extracted from horse . d. The progestin component of CHC is extracted from yams. e. None of the above. WHAT IS CONTRACEPTION MADE OF? In the beginning…

80,000 sow = 5 gallons syrup Mexican yams = 12 mg estradiol & 3 kg 40 mg progesterone via chemical processes called the Marker Degradation Estradiol vs. Ethinyl Estradiol

Estradiol Ethinyl Estradiol Our body’s natural estrogen. More lipophilic and more orally Not very bioavailable when bioavailable. Also much more potent taken orally. Also not easy to at estrogen receptors than estradiol, produce in large quantities. facilitating lower doses. This is the estrogen in almost all CHCs.

Also more lipophilic and more orally bioavailable. Used in Natazia.

Synthetic hormones • Ethinyl estradiol is called an estrogen because it binds to estrogen receptors • There are multiple types of estrogen receptors • Different tissues express different types • Synthetic progestins are called progestins because they bind to progesterone receptors • Again, there are different types of receptors, expressed differently in different tissues • Most synthetic progestins, because they share a great deal of structural similarity with , will also bind to and activate testosterone receptors, called ‘androgenic activity.’ Due to other actions of CHCs, however, the net impact is overall anti- androgenic. • , however, is more similar to , and will oppose testosterone action. 3 mg of drospirenone has approximately the equivalent anti-androgenic of 25 mg of spironolactone. Case

Astara believes strongly in using only natural products and doesn’t want to use anything synthetic. She wonders if there is an all-natural hormonal contraceptive available to her. What do you tell her?

a. The hormones in OC’s are identical to the hormones her body normally makes. b. The hormones in a new pill named Natazia are bioidentical to natural hormones. c. The estrogen component of CHC is extracted from horse urine. d. The progestin component of CHC is extracted from yams. e. None of the above. Case Tina is sexually active and desires birth control, but she is very strongly anti-. She has heard that pills prevent a fertilized egg from implanting and thus could be considered abortive agents. What do you tell her? a. She is correct and should therefore use . b. The primary mechanism of action for CHC is prevention of follicle development. c. The primary mechanism of action of progestin-only pills is prevention of . d. All hormonal contraceptives cause some atrophy of the , but it is not the main mechanism of action for any of them. e. None of the above. MECHANISM OF ACTION http://rhapsodyinj.tumblr.com/post/1592372482/i-recently-found-out-that-some-people-do-not From Jackie, “Lets Be Honest” Mechanisms of action of CHCs

Ethinyl estradiol Progestin • Suppresses FSH/follicular • Suppresses LH/ovulation development • Dose-dependent • Less so in lower dose pills • Atrophies endometrium • Stabilizes endometrium and controls bleeding • Thickens cervical mucous • Potentiates the action of • Disrupts progestins, likely by and peristalsis increasing intracellular • Is the main contraceptive progestin receptors ingredient. • Contributes very little to contraceptive efficacy. Mechanism of Action - DMPA

• High levels of circulating progestin • Completely blocks LH, prevents ovulation • Thickens cervical mucous • Alters the endometrium • Suppresses FSH, although less so than estrogen • No replacement estrogen so overall E levels may be lower • Decline in bone mineral density Mechanism of Action - POPs

• POPs have a lower amount of progestin in them than CHCs, only about 25% of the CHC dose • LH/ovulation are less reliably suppressed • 40% of women on POPs ovulate normally • Rely on cervical mucous changes • Occur about 2-4 hours after dose is taken • Effect diminishes at 22 hours, is virtually nonexistent at 24 hours • Must be taken daily at exactly the same time • If more than 3 hours late, need to use a back-up method x 48 hrs • Higher rates of irregular menstrual bleeding • 40-50% of women will have normal cycles • 40% have short, irregular cycles • 10% have no cycles – spotting, irregular bleeding, or Mechanism – Implant and IUS

• Some suppression of LH/ovulation • Implant blocks ovulation for first 2.5 years but maintains efficacy for 3 • LNG-IUS - 85% of women are ovulatory after the first year • Thickening of cervical mucous • Atrophy of endometrium • LNG-IUS - Up to 90% decrease in menstrual bleeding, >50% amenorrheic at one year • Implant – 21% amenorrheic at 1 yr, 30-40% thereafter, but 20% with frequent or prolonged bleeding • No suppression of FSH or endogenous estrogen • No decrease in bone mineral density Case - answer Tina is sexually active and does not want to get pregnant, but is very strongly anti-abortion. She has heard that birth control pills prevent a fertilized egg from implanting and thus could be considered abortive agents. What do you tell her?

a. She is correct and should therefore use condoms. b. The primary mechanism of action for CHC is prevention of follicle development. c. The primary mechanism of action of progestin-only pills is prevention of ovulation. d. All hormonal contraceptives cause some atrophy of the endometrium, but it is not the main mechanism of action for any of them. e. None of the above. Case

Samantha has a history of morbid treated with a laparoscopic gastric band three years ago. She is taking for her . What do you tell her about her contraceptive options?

a. Due to her surgery, she may not reliably absorb oral methods, so she should choose the patch, ring, injection, implant, or IUD. b. Due to an interaction with her doxycycline, she should avoid oral methods. c. She may use any method she wishes. d. She would do fine on any method except POP, as they are orally absorbed and such a low dose. ABSORPTION & Non-oral Methods • Patch, Ring, Injection, Implant, IUS • Direct absorption through tissues and into the systemic circulation OCs : Absorption from intestines Need intact, functional intestines

CHCs POPs Intestinal Absorption: Vomiting & Diarrhea

• May result in decreased absorption of OC’s and therefore decreased effectiveness • Options: • Use back-up method until on the pill again for a week • Insert pill vaginally*

* Ziaei, Contraception 2002. Souka, Contraception 1986. Coutinho, Fertil Steril 1982 Enterohepatic circulation of EE

40% of dose enters blood • Conjugates of ethinyl estradiol are secreted in the • In the colon, bacteria break them apart • Free ethinyl estradiol is then reabsorbed • This results in a second round of EE absorption • This applies only to EE, not to progestins Enterohepatic circulation &

• use can decrease colonic bacteria, thereby decreasing the amount of free ethinyl estradiol available for reabsorption • This resulted in warnings to pill users that all antibiotics could decrease contraceptive efficacy • Excellent studies have demonstrated that this potential interference DOES NOT occur in any clinically significant way; serum levels are unchanged, there is no increase in ovulation, and there is no decrease in effectiveness CHCs POPs Case

Samantha has a history of morbid obesity treated with a laparoscopic gastric band three years ago. She is taking doxycycline for her acne. What do you tell her about her contraceptive options?

a. Due to her surgery, she may not reliably absorb oral methods, so she should choose the patch, ring, injection, implant, or IUD. b. Due to an interaction with her doxycycline, she should avoid oral methods. c. She may use any method she wishes. d. She would do fine on any method except POP, as they are orally absorbed and such a low dose. Case

Elizabeth has a history of difficult to treat depression but is now doing well on lamotrigene. She would like to start hormonal contraception to treat her . What do you tell her?

a. She should use only non-oral methods such as the IUD, patch, or ring, due to drug-drug interactions from first pass metabolism in the . b. POP will be less effective due to an interaction with lamotrigene. c. CHC use will decrease her blood levels of lamotrigene, so she may need a dose increase of the if she chooses them. First Pass Metabolism

40% of dose enters blood CHC Metabolism in Liver

• CYP 450 • Break down ethinyl estradiol and progestins • CHC use will also induce those enzymes, increasing their activity, and potentially increasing clearance of other drugs as well • Activity can be induced by other drugs, resulting in an increased breakdown of CHCs and reduced effectiveness • CHC induction of P450 enzymes can also facilitate conversions of pro- drugs to active drugs, thus potentiating the action (diazepam, tricyclics, and others) • Multiple different subtypes • Genetic variation in activity Drug-Drug Interactions w/ BC

Decreased effectiveness Decrease effectiveness of BC of other drugs • (Tegretol) • Felbamate • (Lamictal) • Oxcarbazepine • • Phenobarbital • (Dilantin) • Increased effectiveness • Rifabutin of other drugs • Rifampin • Diazepam (Valium) • St. John’s Wort* • Chlordiazepoxide (Librium) • Topiramate • Tricyclics • Vigabatrin • • *Affects bleeding pattern only - Pfrunder 2003 J Clin Pharm Cytochrome karaoke!

• Cythochrome…. They are hepatic enzymes Metabolize estrogen and progestin Conjugate all those drugs and send them away… • They got an interaction… with John’s Wort, Topamax, and Lamictal So mama don’t forget those cytochromes today! US MEC on drug interactions Case - answer

Elizabeth has a history of difficult to treat depression but is now doing well on lamotrigene. She would like to start hormonal contraception to treat her dysmenorrhea. What do you tell her?

a. She should use only non-oral methods such as the IUD, patch, or ring, due to drug-drug interactions from first pass metabolism in the liver. b. POP will be less effective due to an interaction with lamotrigene. c. CHC use will decrease her blood levels of lamotrigene, so she may need a dose increase of the medication if she chooses them. Case Lisa struggles with acne and has heard that OrthoTriCyclen could help. Her mother doesn’t want her to be on hormones, though, because she herself got after starting CHC, and her sister got elevated blood pressure. What do you tell her?

a. CHC do not increase the risk of clinical . b. CHC can increase your risk of gallbladder . c. Only OrthoTriCyclen and Yasmin/Yaz treat acne, so she should use one of those. EE effects on the Liver • Ethinyl estradiol is much more potent than endogenous estradiol at inducing production of hepatic • Increased • Increased SHBG • Decreased free testosterone levels • Usually more than offsets any androgenic activity of the progestin • Helps treat acne, • Increased angiotensinogen • Usually offset by compensatory decrease in renin • Thought to be cause of increased BP seen in some women • Effect can last 3-6 months after discontinuation • In low-dose (<50 mcg)CHC, no increased incidence of HTN EE effects on the Liver/ Gallbladder

• Ethinyl estradiol impairs active transport of biliary components • Higher dose pills were associated with cholestatic jaundice • Ethinyl estradiol increases the cholesterol saturation of bile • Acceleration of gallbladder disease in those already susceptible • Increased incidence of gallstones in the first years of use • Overall no increased incidence in users vs. non

CHCs

Artist: Mieshka / Mike Diliberto Case - answer Lisa struggles with acne and has heard that OrthoTriCyclen could help. Her mother doesn’t want her to be on hormones, though, because she herself got gallstones after starting CHC, and her sister got elevated blood pressure. What do you tell her?

a. CHC do not increase the risk of clinical hypertension. b. CHC can increase your risk of gallbladder disease. c. Only OrthoTriCyclen and Yasmin/Yaz treat acne, so she should use one of those. Case

Diana has PCOS, with acne, hirsutism, and irregular menses. Her mother had a DVT postpartum. She wants treatment for her PCOS but is worried about the risk of clot. What do you tell her?

a. The history of DVT in a first-degree relative is a contraindication to CHCs. b. She should be fine as long as she avoids third- and fourth- generation ( and drospirenone)-containing CHCs. c. If her mother tested positive for a thrombogenic mutation, it would be a good idea for her to be tested for it as well. VENOUS THROMBOEMBOLISM Deep Venous and EE effects on the liver: clotting

• Ethinyl estradiol is much more potent than endogenous estradiol at inducing production of hepatic proteins • Changes that promote clotting • VII, X, fibrinogen increase • APC decrease • Changes that inhibit formation of or break down clots • Plasminogen increases • Antithrombin decreases • In many women, these changes seem to balance each other out, but in some they predispose to clot formation • Estradiol valerate does not induce the same changes in clotting parameters, but we do not yet have any data on clinical outcomes (Junge, Clin Dug Invest. 2011)

Thrombogenic conditions • mutation • Resistance to activated C • Increased risk thrombosis • Heterozygotes have 6-8-fold increased risk • Homozygotes have 80-fold increased risk • Carrier frequency: • 5.3% in Caucasian Americans • 2.2% in Hispanic Americans • 1.25% in Black & Native Americans • 0.45% in Asian Americans

• Should we screen? Leiden, South Holland • Of 10 million women on OC’s, 450k likely have Factor V Leiden Photo: Motumboe • Incidence of VTE is only 4-5 per 100,000 per year in young women • So < 1 in 1000 of those with Factor V will actually have a clinical event • Screen ONLY those with personal or 1st degree relative h/o VTE • Prothrombin mutation • Antiphospholipid antibody syndrome (lupus) • Protein C & Protein S Deficiencies VTE IN CHC USERS • Epidemiologic study of 1524 cases & 1760 controls

• Absolute risk increase of 2.5 per 10,000 women if under 30 • Approximately from 1 in 10,000 to 1 in 2500 (0.012% to 0.037%) Effect of estrogen dose

• Two-fold increased risk seen with 50 mcg pills as opposed to 30 • No decreased risk seen in 20 mcg pills, but numbers were low What about the progestin?

• NO significant effects on clotting parameters in biochemical studies • Yet there are clinical studies that come out every time a new pill formulation is released, showing increased risk of VTE? (desogestrel, drosprienone, etc.) Importance of duration of use Confounding of epi. studies on VTE

• For all CHC users, VTE risk is highest in the first 3-12 months of use (new initiator effect) • A proportionally higher subset of users of new OCPs are new users of BC in general and are at highest risk, therefore, of VTE • Thus, any time a new CHC is released, we should expect to see an increased rate of VTE on that method, as proportionally more of its users are in their first 12 months of CHC use • Evidence of this effect is further supported by 5-year follow up studies that typically show no increased risk of VTE with one method vs. another Type of progestin not significant for VTE risk What if we bypass First Pass?

40% of dose enters blood

What if we bypass first pass?

• Four Danish national registries from 2001-2010 • Total of 9,429,128 woman-years of observation What if we bypass first pass? Adjusted for length of use

Lidegaard. BMJ. 2012 Non-oral route – no advantage

• No evidence of benefit if avoid first-pass metabolism of EE • Biochemical data supports that the vaginal delivery of EE does not make a difference in terms of factors (Sitruk- Ware et al. J Clin Endocrinol Metab June 2007) • In fact, there is a small, yet significant, increase in VTE risk among patch AND ring users compared with OC users • Very small number of patch users makes data less conclusive, especially since patch delivers higher levels of EE • Possible confounding by prescribing preference, esp. for ring Relative risk of VTE

Without COC With COC use 36 31.5 31

26

21 17 16 16

11 8.5 9 7 6 6 4.5 3 3 2 2.5 1 OC use Factor V Travel Surgery Obesity Leiden

Lidegaard. BMJ. 2012 VTE precautions for CHC VTE Precautions for CHC Central

• Woman who develops a persistent, severe after starting CHC, with or without neurologic signs & symptoms • CT scan is often nondiagnostic (no enlargement of ventricles) • Need MRI and often MR venogram to diagnose • Incidence of 6 per million overall • 12 per 100,000 peri- & postpartum • Historically men=women, but since 1970’s, 80% are women • Can be triggered by trauma (head trauma, neurovascular procedures, lumbar puncture) or infection (mastoiditis) • 79% recover, but 8% have minor residual deficits, 5% have severe deficits, 8% fatality rate Case - answer

Diana has PCOS, with acne, hirsutism, and irregular menses. Her mother had a DVT postpartum. She wants treatment for her PCOS but is worried about the risk of clot. What do you tell her?

a. The history of DVT in a first-degree relative is a contraindication to CHCs. b. She should be fine as long as she avoids third- and fourth- generation (desogestrel and drospirenone)-containing CHCs. c. If her mother tested positive for a thrombogenic mutation, it would be a good idea for her to be tested for it as well. Case Vanessa is a 36 year-old nontraditional student with a history of mild hypertension well-controlled with HCTZ 25 mg daily. She does not smoke. She presents to the clinic for a refill of her CHC. Her BP is 115/75. What do you tell her? a. She is at increased risk of serious adverse events on CHCs due to her history of hypertension. b. No problem, as long as her HTN is well controlled. c. No problem, as long as she doesn’t smoke. d. Women over age 35 should not use CHC. ARTERIAL THROMBOEMBOLISM MYOCARDIAL CEREBROVASCULAR INFARCTION (MI) ACCIDENT (CVA) Evaluation of rare events

These events are extremely rare in young women (less than 1 in 10,000), so they are difficult to study. Data sets large enough can only be obtained via epidemiologic study (case-control and incidence rates, not randomized controlled trials). Even with large sample sizes, there can be significant differences in findings between different studies, making conclusions elusive. Summary of Studies of First-Ever Incidence in Women 15 to 35 Years of Age Incidence per 100,000

Reference Place Age, y Cases, n Incidence* Comment Kittner et al5 Maryland, US 15-39, white 12 7.3† Excludes SAH 15-39, black 26 20.5† Guidetti et al6 Bologna, Italy 15-24 1 2.9 … 25-34 6 17.0 Rasteyne et al7 Kaunas, Lithuania 25-34 7 16.0 Low percentage of CT/MRI scans

Czlonkowska et Warsaw, Poland <30 1 1 … al8 Lauria et al9 Belluno Province, Italy <34 0 0 … Petitti. Stroke. 1997; 28: 280-283 Stroke. Petitti. Bonita et al10 Auckland, New Zealand 15-24 NR 4 …

25-34 NR 7 Anderson et Perth, Australia 15-24 2 10 … al11 25-35 3 17 Leno12 Cantabrio, Spain 16-25 3† 7.4 … 26-35 6† 15.3 Bamford et al13 Oxfordshire, UK 15-24 4 10 Includes TIA 25-34 4 12 The importance of age Incidence of MI & CVA by Age

Myocardial Infarction* All Stroke†‡

Age, y Women-Years n Rate§ (95% CI) n Rate§ (95% CI)

15-19 534 579 3 0.6 (0.1-1.6) 8 1.5 (0.6-2.9)

20-24 497 673 1 0.2 (0.0-0.7) 20 4.0 (2.5-6.2)

25-29 552 939 9 1.6 (0.7-3.1) 32 5.8 (3.9-7.9) 1997; 28: 280-283 Stroke. Petitti.

30-34 662 304 10 1.5 (0.7-2.8) 56 8.5 (6.4-11.0)

35-39 693 900 37 5.3 (3.8-7.3) 102 14.7 (12.1-17.7)

40-44 673 406 124 18.4 (15.5-21.8) 179 26.6 (23.0-30.6)

All 3 614 802 184 5.0 (4.4-5.9) 397 10.7 (9.9-12.1)

(Rate is per 100,000) Importance of age

30 26.6 25

20 18.4

14.7 15

MI 1997; 28: 280-283 Stroke. Petitti. 10 8.5 CVA 5.8

Incidence, per 100,000 5.3 5 4 1.5 1.6 1.5 0.6 0.2 0 15-19 20-24 25-29 30-34 35-49 40-44 Age MI : WHO Multicenter Study, Lancet 1997

Myocardial Infarction 600

500 485

400

300 Age < 35 200 Age > 35 Incidence per 100,000 Incidence per 100,000 per year 88 100 40 43 4410 8 0 Nonsmokers Nonsmoker + Smoker Smoker + OC OC NO increased risk of MI seen with OCs in nonsmokers under age 35. MI: Case-Control Study, Circulation 1998

255 cases and 904 controls Mean age of subjects was 39 NO increased risk seen in CHC users Stroke: Case-Control Study

Tzourio 1995 BMJ Case-control study of 72 women with stroke & 173 controls 6

5 4.8 4 No use 50 mcg 3 30-40 mcg 2.7 2 20 mcg 1.7 POP 1 1 1 0 RR of Stroke

All subjects age <45, mean age 35, cases were hospitalized Stroke: Population Study Kaiser Permanente, 1.1 million women, total 3.6 million woman-years, 408 confirmed , looked at effect of low-dose (<50 mcg) CHCs

Petitti Who’s a girl to believe? • 15-year Danish historical cohort study • Women aged 15-49 • Total of 1,626,158 women and 14,251,062 woman-years • 3311 thrombotic strokes • 1725 myocardial infarctions Results Hypothesized change in risk

Myocardial Infarction* All Stroke†‡

Age, y No CHC* CHC* No CHC* CHC*

15-19 0.6 1.2 1.5 3.0

20-24 0.2 0.4 4.0 8.0

25-29 1.6 3.2 5.8 11.6

30-34 1.5 3.0 8.5 17.0

35-39 5.3 10.6 14.7 39.4

40-44 18.4 36.8 26.6 53.2

All 5.0 10.0 10.7 21.4

*worst-case estimates, based on RR 2.0 and assumption that overall incidence rates were only for non-users (Rate is per 100,000) 1997] Stroke. [Petitti. from on data based My calculations, MI & CVA Conclusions

• There appears to be a small increase in risk in CHC users, especially when studying a population with a high prevalence of Factor V Leiden • RR 1.3-2.3 for MI • RR 1.2-2.2 for CVA • Absolute risk is still very low in college-aged women • 1 in 100,000 for MI • 1 in 20,000 for CVA • Risk increases with age • Need to consider additive and/or synergistic effects with other risk factors • No increase in risk seen in any of the progestin-only methods Importance of risk factors MI CVA CVA Petitti MI WHO if>35 9 8 8 7.8 7.2 7

6

5 4.6

Relative Risk Relative 4 3.6

2.7 2.7

3 Lidegaard 2012, Petitti NEJM 1997 1996, WHO Lancet NEJM 2.3 2.1 2.2 1.8 1.9 2 1.7 1.6 1 1 OCP use Lipids HTN Smoking MEC Precautions for Arterial Dz. MEC Precautions for Arterial Dz. Incidence per 100,000 women age 15-24, by exposure

50 45 43 43 40 35 30 Non-Users 25 CHC users 20 Pregnancy 14.5 15 10 5 5

5 2.5 and cdc.gov/nchs/data Lidegaard, Pettiti, Speroff, 0.5 1 1 0 MI CVA Death* *Death rates for pregnancy are pregnancy-related ONLY. Death rates for pill users and nonusers are all-cause, including those not related to exposure. About half of all deaths in this age group are due to accidents. Case - answer Vanessa is a 36 year-old nontraditional student with a history of mild hypertension well-controlled with HCTZ 25 mg daily. She does not smoke. She presents to the clinic for a refill of her CHC. What do you tell her? a. She is at increased risk of serious adverse events on CHCs due to her history of hypertension. b. No problem, as long as her HTN is well controlled. c. No problem, since she doesn’t smoke. d. Women over age 35 should not use CHC. Case

Caitlin has a history of , and sees funny gray spots in her vision before her headaches happen. What are her contraceptive options?

a. She can use any method, as her absolute risk of stroke is extremely low. b. She should not use any estrogen- containing method due to the increased risk of stroke. c. Birth control pills are contraindicated, but she can use the Ring, as the estrogen levels are so much lower and it avoids first-pass metabolism. d. She should use an estrogen-containing method, as that will help control her headaches. Migraine • Thought to be a primary brain disorder, classified as neurovascular headache • Disruption of normal triage of afferent signals • Leads to hyperemia then oligemia of brain • Possible sterile inflammatory response • Pain via ophthlamic branch of trigeminal and/or C2 • Evidence for roles of estrogen and progestin • Clinical • Prepubertal incidence male=female, postpub. female>male 3:1 • Menstrual migraine • Low migraine incidence in 3rd trimester pregnancy • Biologic • Genetic mutation in gene increases migraine risk • Genetic mutation in progesterone receptor gene also increases risk • Estrogen receptor increases NO synthase activity in endothelial cells • E receptors also influence serotonin synthesis and degradation • Plamsa beta-endoprhin and cortisol responses are impaired during luteal phase

Brandes, JAMA. 2006;295:1824-1830 and Goadsby, NEJM. 2002;346,4:257-270 Migraine & Stroke

Relative Risk of Stroke, by Exposure 16 14 14 12 10 10 8 6.2 6 3.5 4 3

2 1 0 Baseline Migraine Migraine w Migraine + Smoker Smoker w aura OCPs migraine

Tzourio. BMJ. 1995. Stroke, Migraine, & CHCs

• Absolute risk of stroke in young women is 10/100k overall • 6 in 100,000 for women w/o migraine • 19 per 100,000 for women with migraine • 36 per 100,000 for women with migraine with aura • US MEC designates migraine: • w/ aura as Category 4 for CHC at any age • w/o aura Cat. 3/4 if age >35 Case - answer

Caitlin has a history of migraine headaches, and sees funny gray spots in her vision before her headaches happen. What are her contraceptive options?

a. She can use any method, as her absolute risk of stroke is extremely low. b. She should not use any estrogen- containing method due to the increased risk of stroke. c. Birth control pills are contraindicated, but she can use the Ring, as the estrogen levels are so much lower and it avoids first-pass metabolism. d. She should use an estrogen-containing method, as that will help control her headaches. Case

Beverly wants a reliable, safe contraceptive. She has sickle cell anemia and takes daily iron supplements. Her periods are heavy, and her hematocrit runs around 32. What do you tell her?

a. CHCs will decrease menstrual bleeding and therefore help her anemia. b. DMPA will decrease her sickle crises as well as decrease her bleeding. c. LNG-IUS would be a low- maintenance option that would also decrease uterine bleeding. d. All of the above. NON-CONTRACEPTIVE BENEFITS Physiologic actions and benefits

Suppresses Suppresses Inhibits Thickens Thins Increases HPA follicular ovulation cervical endomet- SHBG develop- mucous rium ment CHC+++++++++ DMPA++++++++- LNG IUS - - + + ++ - Implanon+-+++- POP - - - + + - PMDD Ovarian Ovarian PID Endomet- Acne Protection Menstrual cysts CA rial CA Hirsutism against Ovarian Endomet- CA riosis Menorr- haghia Estrogen – the triple threat!

• Regulates bleeding • Irregular menses • Menorrhaghia • Dysmenorrhea • • Anti-androgenic via ovarian suppression & increased SHBG • Acne • Hirsutism • Follicle suppression • Symptomatic cysts Treatments for PCOS

Irregular Endomet. Acne/ Insulin Infertility menses CA risk Hirsutism resistance Diet & +++++ Exercise CHCs +++ +++ ++ - - Cyclic + +++ - - - Provera Metformin + + - ++ + Prog-Only + +++ - - - Spirono- --++-- lactone CHC – Delivery Options

• Oral • Require daily dosing but more forgiving than POPs • Highly familiar to patients • Can do extended/continuous cycling • Vaginal • Insert for 3-6 weeks, then ring-free week • Can do extended/continuous cycling • • Convenient • Higher dose of EE overall • New patch coming in 2013 or 2014 with lower dose • Injection • Cyclofem/Lunelle is being revived, will be available in a few years Progestin-only benefits & risks • ALL – safe for migraine with aura, increased VTE, MI, or CVA risk • ALL – decreased risk of • Progestin-Only Pills • Easy access • Need to take at same time every day • DMPA • Highly effective but not easily reversible • Lower seizure incidence • Lower sickling risk • Decreased menstrual bleeding • No concern about drug interactions due to high dose • Decreased bone density • LNG-IUS • Highly effective & Convenient • Long-acting & Easily reversible • Decreased menstrual bleeding • Very low risk of drug interactions • Implanon • Highly effective & Convenient • Long-acting & Easily reversible • High rates of irregular bleeding Case - answer

Beverly wants a reliable, safe contraceptive. She has sickle cell anemia and takes daily iron supplements. Her periods are heavy, and her hematocrit runs around 32. What do you tell her?

a. CHCs will decrease menstrual bleeding and therefore help her anemia. b. DMPA will decrease her sickle crises as well as decrease her bleeding. c. LNG-IUS would be a low- maintenance option that would also decrease uterine bleeding. d. All of the above. PUTTING IT ALL TOGETHER In summary…

• Hormonal contraceptives are overall very safe but are associated with some risks. The most serious risks are due to the estrogen component and therefore exist only for CHC. • No reduction in risk seen with non-oral CHC methods • Contraceptives also have many non-contraceptive benefits • Control or lessening of menstrual bleeding and cramping • Control of acne and hirsutism • Control of ovarian cysts and endometriosis • 50% Reduction in risk of endometrial and • Reduction in risk of PID • Reduced seizures and sickle crises with DMPA • Remember factors that affect absorption & metabolism • Intestinal factors for oral methods • CYP450 In closing… Questions to always ask

• Safety criteria: • Age • Current medications • Smoking • Hypertension • Migraine? With aura? • VTE or family history of VTE • Lupus • Diabetes • Bariatric surgery? Malabsorptive or restrictive? • Patient goals, aside from contraception • Acne, hirsutism, dysmenorrhea, PMDD, menorrhagia, cysts • Patient preferences • Convenience, ease of use, cost, effectiveness Thank you! Questions for me?

Pharmacology of ethinyl estradiol

• Ethinyl estradiol is orally bioavailable as it is not as fully metabolized in first pass in the liver (as estradiol is) • Absorption • Absorbed from the small intestine, transported to liver • In the liver, about half is metabolized into glucuronide and sulfate conjugates and secreted in the bile into the intestine • In the intestine, bacteria break apart some of the conjugates, and more ethinyl estradiol is then reabsorbed • Initial peak at two hours, and a second peak slightly later due to enterohepatic circulation and reabsorption as above • Timing and magnitude of second peak depend on host’s bacterial flora • Rapidly metabolized • cleared by the body in 13-27 hours (ave. t1/2 is 7.7 hours) • cytochrome p450 3A4 system • excreted in both and urine • Highly bound to plasma albumin • Activates estrogen receptors, therefore is considered an “estrogen” Rapid clearance of ethinyl estradiol Physiologic actions of EE

• Pituitary suppression • Decreased ovulation • Decreased ovarian production of estrogen, progesterone, and testosterone • Increase in binding globulin • Regulation of endometrial lining • Increase in thrombotic factors – Factors VII, X, and fibrinogen Other actions of CHCs

Ethinyl estradiol Progestin • Increases clotting factors • May be androgenic or • Increases SHBG antiandrogenic • Induces CYP450 • May decrease SHBG • Increases angiotensinogen What about DMPA?

• >3-fold increased risk of DVT compared with non- users • Data confounded • Higher BMI in DMPA users (25.5. vs 24.8) • Higher rates of smoking in DMPA users (50% vs 31%) • When corrected, OR is still elevated, at 3.0 • Limited by small numbers Why not warn them just in case?

• Women who believe that their pill isn’t working tend to stop taking it • This results in confusion as to when and how to restart • Due to the interruption, there can then be a window wherein ovulation will occur, and women may not realize that the pill will not be effective again just as soon as they restart it • Women who aren’t accustomed to using condoms are often less adept or conscientious about using them • Warning women about potential decreased effectiveness with common antibiotics is: • Unnecessary • Associated with higher rates of unintended pregnancy

Don’t do it! Case

Natasha recently heard a news story about a young woman who suffered a stroke, believed to be due to birth control pills. She is wondering if she should stop her CHC. What do you tell her?

a. CHC do not increase risk of stroke in any statistically significant way. b. Only high-dose CHC are associated with an increased risk of stroke. c. As long as she doesn’t use the Ortho Evra patch, she should be fine. d. The data is not conclusive, but there does seem to be a small increase in risk of stroke in CHC users. Case #

Anna is referred by her dermatologist for consultation about contraceptive options, as she is about to start chronic antibiotic therapy for her acne. What do you tell Anna?

a. She needs to use condoms at all times as antibiotics make birth control less effective. b. Antibiotics will make OCs less effective, due to decreased enterohepatic circulation, but she can use the Ring, Patch, DMPA, LNG-IUS, or Implanon. c. She can use any from of BC she chooses – typical antibiotics will not make them less effective. d. Antibiotics will interfere only with POPs, as they are such a low-dose method. Incidence per 100,000 women < 30, by exposure

200 180 172 160 140 120 Non-Users 100 CHC users 80 Pregnancy 60 40 37

20 Speroff 6 0 DVT Crude rate of VTE per exposure

12

10 9.7

8 7.8

6 5.3

4

2 1.7 Rate per 10,000 woman-years Rate 2 1.4

0 No BC Pills Patch Ring Implant LNG-IUS Lidegaard. BMJ. 2012 Pathway to pregnancy

Healthy, happy, Delivery of sperm into vagina Unobstructed path from numerous sperm vagina to fallopian tubes Pathway to Pregnancy

Fertilization Formation of zygote Implantation and successful cell division HOW DOES BIRTH CONTROL WORK? Pathway to Pregnancy

Functional hypothalamic- Robust ovum, ovulation pituitary axis Corpus luteum, Receptive endometrium