Evolution of Contraception: Potions to Progestins

Jennifer McDonald DO

Basics

• 48% pregnancies in the US are unintended • Age group with second highest rate of unintended pregnancy is women 40-44 • Half of all unintended pregnancies end in abortion • 45% of abortions occur in women 25-30 years old and 24% occurred >30 years old

Pregnancy Prevention

Lactational Amenorrhea (LAM) •Typical use 95% • Perfect use 98% Natural Family Planning • 78-88% No method • 15%

Ancient “Technology”

• Vaginally administered honey • Drinking the water used to wash the dead • “Sponges” made from crocodile dung or fermented dough • Lemon wedges over the cervix • Middle Ages women died of lead, arsenic, mercury, or strychnine poisoning after drinking for theoretical contraceptive or abortifacient effects • Earwax of a mule worn as an amulet to ward off pregnancy

“Modern” Contraception

• 1930s Austrian physiologist suggested extracts of ovarian hormones could inhibit fertility • Researched hampered by unavailability of hormones • 1960s FDA approved first oral contraceptive • Estimates suggest that by the end of their reproductive years 80% of US women will have used OCs for an average of 5 years

Development of Non-hormonal Means

• First IUD made of silk suture in 1929 reported a 3% pregnancy rate • 1930s rings wrapped in silver wire 1.6% pregnancy rate • 1960s first copper IUDs introduced • 1980s litigation involving Dalkon Shield led to decrease in IUD use • Today IUDs used by 2% US women • 2 available forms: Progesterone (Mirena/Progestasert) and copper (Paraguard)

Barrier Methods

• Condoms (male & female) • Diaphragm (used by <2% of women) • Cervical cap (no longer available in the US) • Contraceptive sponge

Progestin Only Options

Injection Depo Provera Intrauterine Devices Mirena – good for up to 5 years Progestasert – inserted yearly Implants Implanon – good up to 3 years

Mechanism of Action Progestin Only Forms

• Blocks LH • Maintains thickness of cervical mucous • Reduces mobility of fallopian tubes • Changes uterine lining making it unfavorable for implantation

Side Effects Progestin Only

• Headache • Vaginitis • Breast pain • Weight gain • Acne Most disappear within a few months of starting

Depo Provera

• FDA approval for contraception in 1991 • Given as an IM injection every 11-13 weeks • Suppresses ovulation • Depresses ovarian steroidogenesis • Estradiol can dip into menopausal ranges leading to increased bone mineral resorption • Continuous use should not exceed 2 years (not lifetime) • Menstrual changes • 50% amenorrheic by 12 months • 75% amenorrheic by 24 months

Depo Provera cont.

• Weight gain more variable than with other methods • Return to fertility can be delayed (median 9 10 months) • May be used in breast feeding • May be used in women with contraindications to estrogen containing products (eg. Smokers over 35, thrombophilias)

Implanon

•Available in Europe and Asia for 8 years and used by 2 million women •Easier insertion and removal than its predecessor Norplant •99% efficacious (Pearl index 0.38)

Implanon

• Single 4 cm rod implant (Etonogestrel) • Implanted subdermally in the upper arm • No meaningful effects on lipids, carbohydrate metabolism, liver function, blood pressure, thyroid or adrenal function

Advantages

Implanon

Disadvantages • Dysmenorrhea relief in 88% of women • Safe in breast feeding • High efficacy • No abortifacient properties • Long term use • Does not suppress estradiol levels • Requires minor surgical procedure • Lack of protection against STDs • Bleeding irregularities Infrequent bleeding (27%) Amenorrhea (18%) Prolonged bleeding (15%) Frequent bleeding (7%) • Weight gain

Progesterone IUDs

• Introduced in the US 2002 • Approved for 5 years of use • 5 year failure rate 0.7% • Actions primarily local (thickens cervical mucous) • Ovulation not usually impaired • Rapid return to fertility • Long term effects on endometrium • By 12 months bleeding reduced 70-90% • Majority of women amenorrheic at one year • Useful in patients with dysmenorrhea and menorrhagia Mirena Copper

IUD Mechanism of Action

Mirena & Cycle Effects

Who Shouldn’t Use the IUD

• History of pelvic inflammatory disease • Copper allergy (Copper IUDs only) • Multiple sexual partners • Uterine abnormalities • Untreated infections of the cervix or uterus • History of ectopic pregnancy

Oral Contraceptives

• Combination of ethinyl estradiol and one of several progestins or progestin alone Mechanism of Action • Inhibit the LH surge needed for ovulation (progestin) • Modulating GnRH release/FSH production (estrogen) • Alter cervical mucous • Induce atrophic changes in the endometrium

Estrogen Pharmacokinetics

Naturally occurring estrogens • Readily absorbed by GI tract, skin and mucous membranes • Also fairly well absorbed when given IM • Partially inactivated by P450 system Synthetic estrogen analogs • Well absorbed by GI tract, skin and mucous membranes • Fat soluble stored in adipose tissue • Prolonged action and higher potency than natural estrogens

Progesterone Pharmacokinetics

• Rapidly absorbed after administration by any route • Short half life • Almost completely metabolized after one passage through the liver • Synthetic progestins less rapidly metabolized Adverse Effects Edema/depression/Increase LDL:HDL

Disadvantages of Estrogen

• Even for healthy users slight increase of blood clots • For smokers over the age of 35 this risk is dramatically increased • Contraindicated in women with history of certain forms of cancer

Contraindications to Estrogen Containing Contraceptives

• Migraine with aura • Smokers over the age of 35 • History of thromboembolic disease • Coronary artery disease • Diabetes or hypertension with vascular disease or older than 35 • Lupus erythematosus • Hypertriglyceridemia

OCs – Noncontraceptive Benefits

• Lower incidence of endometrial and ovarian cancers • Fewer ovarian cysts • Decreased risk of ectopic pregnancy • Minimize acne • Regulation of menses – lighter flow • Reduction in dysmenorrhea • Reduction in symptomatic fibrocystic breast disease • Decrease upper genital tract infection (PID)

OCs – Disadvantages

• No protection against STDs • Increase in thromboembolic events • Compliance issues • Nausea/weight gain/breast tenderness • May precipitate migraine headaches

Oral Contraceptives

• Combination pills • Progestin only pills • Post-coital (Emergency) contraception Mechanism of Action Suppression of ovulation by feedback inhibition of endogenous estrogen

Combination Formulations

• Estrogen prevents ovulation • Progestin prevents implantation and makes cervical mucus impenetrable to sperm Monophasic Triphasic Extended Cycle • Perfect use efficacy 99% • Rapid return to fertility on discontinuation Ethinyl estradiol* Estrogen in 99% of all OCPs

Ortho Evra

• Introduced in 2002 • Combination estrogen/progestin • Inhibits ovulation similar to OCPs • Each worn for 1 week at a time for 3 consecutive weeks • Fourth week is patch free • Return to fertility within one month • Weight > 198 pounds associated with higher pregnancy rates

Nuva Ring

• Introduced in mid-2002 • Combination therapy • Half the estrogen dose than traditional oral contraceptives • Inserted at the top of the vagina • Slow, continuous release of hormone over a 3 week period • Return of fertility within one month

Progestin Only Pills

• “Mini-pill” • Safe in breast feeding • Ovulation not necessarily affected • Must be taken at the same time every day to ensure effectiveness

Improper Counseling

• 42% women will discontinue method without consulting health care provider • Poor compliance • 47% users miss one or more pills/cycle • 22% miss two or more

Emergency Contraception

• High dose estrogen/progestin administered within 72 hours of unprotected intercourse • Two doses 12 hours apart • Single mechanism of action not identified • Inhibition or delay of ovulation • Histologic/biochemical changes in the endometrium • Alterations in tubal transport • 98% patients will menstruate by 21 days after treatment

Emergency Contraception

Preven Emergency Contraceptive Kit Plan B • High incidence of nausea & vomiting • Effectiveness rate 75% If 100 women had unprotected intercourse in the middle two weeks of their cycle 8 would become pregnant. Use of emergency contraception would reduce this number to 2 (75% reduction)

Nutrition & Hormonal Contraception

Hormonal Contraception & Cancer

Ovarian Cancer Cervical Cancer • Reduces risk by 30-50% • Even in women with genetic predisposition • Believed to be due to progestin component • Unknown whether increased risk arises from true oncogenic effect or discontinued condom use and risk taking behavior (increased risk of HPV acquisition) • Protection after 5 years of use and persists for up to 20 years Breast Cancer • Studies conflicting Uterine Cancer • Reduces risk by 40-50% • Risk was higher with older higher dose pills • Study in 2002 no association between Ocs and breast cancer after 15 years of use

Surgical Sterilization

• One of most common methods of contraception in the US (25%) • In every case should be considered permanent • Patency of fallopian tube disrupted by excision, ligation, cauterization, or occlusion by rings or clips • 10 year failure rates range from 0.75% to 3.65% • Male sterilization involves disruption of vas deferens • First year failure rate 0.15%

Essure Tubal Occlusion

• Available in the US since 2002 • Micro-insert composed of stainless steel inner coil, nitinol elastic outer coil and PET fibers • Inserted in the proximal section of each fallopian tube under hysteroscopic guidance • Elicits an intended benign occlusive tissue response • Clinical trials 2 year failure rate 0%

Essure

Essure Follow-up

Dye spillage Normal HSG Abnormal HSG

Essure Advantages

• Non-incisional • Non-hormonal • Can be performed without general anesthesia • Rapid recovery - discharged 45 minutes after and 92% returned to work the next day • Highly effective • Available to patients with not eligible for invasive sterilization

Essure Disadvantages

• Chance that both micro-inserts can not be placed (14% in clinical trials) - 83% were placed on second attempt • Must rely on back-up contraception for 3 months • Removal of inserts requires surgery and may result in hysterectomy

Natural Family Planning

Fertility Awareness Methods • Basal body temperature • Ovulation method • Symptothermal Success based on: • Method’s accuracy in determining fertile days • Ability to comply with method diligently • Couple’s ability to avoid intercourse on fertile days

Ovulation Method

Billings Method • Monitoring cervical secretions • Avoid unprotected intercourse during preovulatory days until the 4th day after the “peak” secretions day (last day of watery discharge)

Symptothermal

• Observation of cervical secretions as well as taking basal body temperatures • Avoidance during peak fertility days

Standard Days

• Based on physiology of the menstrual cycle & functional life span of the sperm and ovum • Best for women with cycle length between 26 and 32 days • Pregnancy only likely on Days 8-19 • 5% Failure rate • 12% Typical use failure rate • Intercourse 5 days prior to ovulation 4% probability • 2 days preceding ovulation 25-28% • 24 hours after 8-10% • Day after 0%