Understanding Hormonal Contraception Alexandra Hall MD University of Wisconsin, Stout ACHA 2013

Disclosures • I will discuss off-label use of medications. • I have no financial conflicts of interest.

Overview • Mechanisms of Action • Risks & benefits, based on pharmacology & physiologic effects • Safe prescribing, weighing the options

Abbreviations • CHC = Combined Hormonal Contraceptive • Estrogen + Progestin • Pills, Patch, & Ring

• • • • • • • •

BC = Birth Control OC = Oral Contraceptive (COC=Combined Oral Contraceptive) POP = Progestin-Only Pills, a.k.a. Mini-Pills LNG-IUS = Levonorgestrel Intrauterine System (Mirena IUD) DMPA = Depot-medroxyprogesterone acetate (Depo-Provera) EE = Ethinyl estradiol SHBG = sex hormone 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 Infertility • 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 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.

WHAT IS CONTRACEPTION MADE OF?

In the beginning… 80,000 sow ovaries = 12 mg estradiol & 40 mg progesterone

5 gallons syrup Mexican yams = 3 kg progesterone via chemical processes called the Marker Degradation

Estradiol vs. Ethinyl Estradiol

Estradiol Our body’s natural estrogen. Not very bioavailable when taken orally. Also not easy to produce in large quantities.

Ethinyl Estradiol More lipophilic and more orally bioavailable. Also much more potent at estrogen receptors than estradiol, facilitating lower doses. This is the estrogen in almost all CHCs.

Also more lipophilic and more orally Estradiol Valerate 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 testosterone, will also bind to and activate testosterone receptors, called ‘androgenic activity.’ Due to other actions of CHCs, however, the net impact is overall antiandrogenic. • Drospirenone, however, is more similar to spironolactone, and will oppose testosterone action. 3 mg of drospirenone has approximately the equivalent anti-androgenic potency 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-abortion. She has heard that pills prevent a fertilized egg from implanting and thus could be considered abortive agents. What do you tell her? a. b. c. d.

e.

She is correct and should therefore use condoms. The primary mechanism of action for CHC is prevention of follicle development. The primary mechanism of action of progestin-only pills is prevention of ovulation. All hormonal contraceptives cause some atrophy of the endometrium, but it is not the main mechanism of action for any of them. 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 development

• Suppresses LH/ovulation

• Less so in lower dose pills

• Atrophies endometrium • Thickens cervical mucous • Disrupts fallopian tube secretion and peristalsis • Is the main contraceptive ingredient.

• Stabilizes endometrium and controls bleeding • Potentiates the action of progestins, likely by increasing intracellular progestin receptors • Contributes very little to contraceptive efficacy.

• Dose-dependent

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 amenorrhea

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. b. c. d.

e.

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

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.

b. c. d.

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

ABSORPTION & METABOLISM

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 bile • 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 & Antibiotics • Antibiotic 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.

b. c. d.

Due to her surgery, she may not reliably absorb oral methods, so she should choose the patch, ring, injection, implant, or IUD. Due to an interaction with her doxycycline, she should avoid oral methods. She may use any method she wishes. 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 dysmenorrhea. What do you tell her? a.

b. c.

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. POP will be less effective due to an interaction with lamotrigene. CHC use will decrease her blood levels of lamotrigene, so she may need a dose increase of the medication if she chooses them.

First Pass Metabolism 40% of dose enters blood

CHC Metabolism in Liver • CYP 450 enzymes • 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 prodrugs 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 of other drugs

Decrease effectiveness of BC

• • • • • • • • • • • •

Carbamazepine (Tegretol) Felbamate Oxcarbazepine Phenobarbital Phenytoin (Dilantin) Primidone Rifabutin Rifampin St. John’s Wort* Topiramate Vigabatrin Griseofulvin

• Lamotrigine (Lamictal) • Phenobarbital Increased effectiveness of other drugs

• • • •

Diazepam (Valium) Chlordiazepoxide (Librium) Tricyclics Theophylline

*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.

b. c.

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. POP will be less effective due to an interaction with lamotrigene. 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 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.

EE effects on the Liver • Ethinyl estradiol is much more potent than endogenous estradiol at inducing production of hepatic proteins • Increased cytochrome P450 • Increased SHBG • Decreased free testosterone levels • Usually more than offsets any androgenic activity of the progestin • Helps treat acne, hirsutism

• 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 (3-fold increased risk of DVT compared with nonusers • 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. b. c. d.

CHC do not increase risk of stroke in any statistically significant way. Only high-dose CHC are associated with an increased risk of stroke. As long as she doesn’t use the Ortho Evra patch, she should be fine. 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. b.

c. d.

She needs to use condoms at all times as antibiotics make birth control less effective. Antibiotics will make OCs less effective, due to decreased enterohepatic circulation, but she can use the Ring, Patch, DMPA, LNG-IUS, or Implanon. She can use any from of BC she chooses – typical antibiotics will not make them less effective. 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 37

40 20

6

0 DVT

Speroff

60

Crude rate of VTE per exposure Rate per 10,000 woman-years

12 9.7

10

7.8

8 6

5.3

4 2

2

1.7

1.4

0 No BC

Pills

Lidegaard. BMJ. 2012

Patch

Ring

Implant

LNG-IUS

Pathway to pregnancy

Healthy, happy, numerous sperm

Delivery of sperm into vagina

Unobstructed path from vagina to fallopian tubes

Pathway to Pregnancy

Fertilization

Formation of zygote and successful cell division

Implantation

HOW DOES BIRTH CONTROL WORK?

Pathway to Pregnancy

Functional hypothalamicpituitary axis

Robust ovum, ovulation Corpus luteum, Receptive endometrium