Hormonal Contraception

Adolescent Gynecology

0031-3955/89 $0.00

+ .20

Hormonal Contraception Robert B. Shearin, MD, * and James R. Boehlke, MDt

Increased sexual activity among adolescents and young adults demands that the adolescent health care provider have a thorough understanding of contraception. The topic of hormonal contraception is now extremely relevant because it is well documented that sexual activity among adolescents is increasing as the average age of first intercourse is decreasing. 49 Pregnancy occurs in one of ten women between the ages of 15 and 19 years each year; of these three of four pregnancies are unintended. 22 Furthermore, 500,000 unwanted teenage pregnancies ended in abortion in the United States in 1979, further indicating the need for better education and improved understanding of the use of contraceptives. Hormonal contraception (i.e., oral contraceptives [OCs]) is the most popular method among adolescents who use effective contraception. 32 Unfortunately, many misunderstandings regarding the safety of oral contraceptives exist. 4 This fact, coupled with the common incidence of minor complications, has led to poor compliance and discontinuance in 25 to 55 per cent of teen users.32 The physician working with adolescents must be prepared to advise them about sexuality and contraception. Although individual health care providers might elect not to prescribe contraceptive methods, the ethical and moral implications of contraceptive use are beyond the scope of this article. Despite controversy regarding appropriateness of contraception and profound differences in individual philosophy, the health care provider must be prepared to discuss birth control routinely when treating adolescents in a clinical setting. In this article, the background physiology, risks and benefits, and administration of hormonal contraceptive methods are discussed, with the purpose being to provide relevant information for use in advising and managing sexually active adolescents. 11 HISTORY

The development of the hormonal approach to contraception spans almost 100 years and is still evolving. 19 In 1897 Beard postulated that *Professor of Pediatrics; Director, Pediatric Ambulatory Services, and Division of Adolescent Medicine, Georgetown University, Washington, D.C. tFellow, Division of Adolescent Medicine, Georgetown University, Washington, D.C.

Pediatric Clinics of North America-Vol. 36, No.3, June 1989

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inhibition of ovulation during pregnancy was caused by the corpus luteum; soon thereafter Haberlandt showed that luteal extract made rabbits infertile. The structure of progesterone was defined in 1934 by Corner and Beard, and soon oral progestins were synthesized by Inhoffman and Djerassi. Investigations by Makepeace revealed that pure progesterone of luteal extraction inhibited postcoital ovulation in rabbits. Inhibition of ovulation was introduced into clinical practice by Sturgis and Albright using intramuscular estradiol-benzoate. By 1956, Rock et al. reported that the oral progestin norethynodrel successfully inhibited ovulation in a series of clinical studies. Subsequently, the first effective OC was introduced by Searle as Enovid and was approved for use by the Food and Drug Administration in 1960. This, the "first pill," contained 9.85 mg norethynodrel and 150 I-Lg mestranol, very large dosages of steroids by today's standards. By the late 1960s the scientific community recognized that most of the serious complications were estrogen related. Knowledge of the effectiveness, side effects, complications, and benefits has grown rapidly, and the preparations have been changed substantially. OCs today contain five to ten times less estrogen and progesterone than were present in the 1960s and early 1970s. 41 Studies of more recent preparations indicate that a trend toward lower dosages has reduced the frequency of serious complications and confirmed that current hormonal contraception is a safe and effective means of birth control. 4 Despite continuing advances in hormonal contraceptive technology, public attitudes toward OC use continue to be one of suspicion. A 1985 Gallup Poll revealed that 75 per cent of U.S. women believe OCs carry health risks; 50 per cent believe that infertility is a serious risk in younger women, and 30 per cent feared that OC use would cause cancer.16 Recent studies of low-dose OC use do not support these fears. 4, 7, 16, 19, 23 Hormonal contraceptive technology continues to evolve positively. By using decreaSing dosages, sequential dosages, multiphasic preparations, and progestin-only preparations, OCs today are safer and more reliable. Other avenues of hormone delivery are being developed and tested as progestinelaborating injectables, implants, and vaginal devices. These devices are exerting an impact on contraception worldwide. Hormonal contraceptive technology is approaching the ideal contraceptive-one that reliably prevents unwanted pregnancy with minimal physical and metabolic side effects.

PRINCIPLES OF HORMONAL CONTRACEPTION Normal Physiology The basic events of the menstrual cycle must be understood in order to appreciate how hormonal contraception works. Ovulation results from a complex interaction of hormonal and neuroendocrine events. An average menstrual cycle of 28 days begins with the menstrual phase (days 1 to 4), during which sloughing occurs. The proliferative phase of the menstrual cycle (days 5 to 14) is characterized by uterine endometrial development, follicular development, endometrial thickening, and proliferation of uterine

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glands and vessels. This phase is promoted by increased estrogen levels, decreased follicle-stimulating hormone (FSH) levels, stable luteinizing hormone (LH), and minimal progesterone levels. Triggered by a surge in estrogen, FSH, and LH, ovulation occurs on day 14. This event begins the secretory phase of the menstrual cycle (days 14 to 28). Whereas the proliferative (follicular) phase is dominated by estrogen, the secretory (luteal) phase is dominated by progesterone. The hormones elaborated by the corpus luteum support the secretory phase, which is characterized by endometrial thickening, branching of glandular tissue, and increased secretions by uterine glands. If the ovum is not fertilized, atrophy of the corpus luteum occurs 10 to 12 days after ovulation, resulting in a rapid decline in progesterone and estrogen levels. The integrity of the endometrium, therefore, cannot be maintained, and sloughing of the uterine lining (menses) occurs.

MECHANISM OF ACTION The contraceptive effects of estrogenic compounds are manifest by modifications of normal patterns of ovulation, implantation, ovum transport, and degeneration of the corpus luteum. Ovulation is inhibited by the central effect of estrogen on the hypothalamus and a subsequent suppression of FSH and LH released from the pituitary. Inhibition of ovulation may be evidenced by an absence of midcycle surge of estrogen, FSH, and LH; events that ordinarily trigger ovulation. Suppression of the normal increase of postovulatory serum progesterone is measurable with concomitant decrease in urinary pregnanediol. This suppression of estrogen surge is generally accepted as the primary mode of action of the OC. However ovulation is not always suppressed; OCs containing less than 50 fJ-g of estrogen are 95 per cent to 98 per cent effective in 1!uppressing ovulation. The risk of ovulation increases with missed OC doses and decreased dosages of estrogen. Normal implantation of the fertilized ova is inhibited by highdose estrogens via the antiprogesterone effect of estrogen on the endometrium. Alterations in normal secretory development and cellular density are seen. These changes occur during the interval between conception and implantation, approximately 5 to 7 days. This antiprogesterone effect is the basis for using high-dose estrogen for postcoital contraception. Estrogenic agents also have been shown to accelerate ovum transport with uncertain contraceptive effects. Accelerated degeneration of the corpus luteum is another possible effect of high-dose estrogen, preventing normal implantation and placental attachment. Normally, progesterone (from pro meaning on behalf of, and gestation meaning pregnancy) prepares the endometrium for implantation and maintains pregnancy. However, continual administration of progestin, as in combined oral contraceptives, has several contraceptive effects. Inhibition of ovulation results from progestin-mediated disruption of hypothalamicpituitary gonadotrophin release. FSH and LH release are blunted, thus inhibiting ovulation. Ovum transport is slowed when progestins are present during the early menstrual cycle. If ovulation occurs, chronic progestin

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exposure promotes a resting, atrophic endometrium that inhibits implantation. This effect is used by intrauterine devices (IUDs), which contain slowly released progestin. Progesterone also affects the endometrial environment. Capacitation, which normally occurs in the uterus and oviducts, is partially impaired by the influence of exogenous progesterone. The cervical mucus is also affected; progesterone promotes scanty, thick, cellular mucus that exhibits decreased ferning and spinnbarkheit. This hostile cervical mucus decreases sperm transport and decreases the penetration of the mucus by spermatozoa, thus preventing fertilization. Hormonal contraception is the most effective nonsurgical method of birth control. Only Norplant implants, Depo-Provera injections, and levonorgestrel IUDs have a lower user failure rate than OCs. The lowest firstyear failure rate reported in OCs is 0.5 per cent. 22 Low-dose OCs «50 flg estrogen) taken approximately the same time each day, result in a failure rate of fewer than 1 pregnancy per 100 women-years. The Royal College of General Practitioners study reported a failure rate over time of 0.34 per 100 women-years. 44 A recent evaluation of multiphasic OC suers revealed a product failure rate of 0.22 pregnancies per 100 women-years. 14 Usually no more than 50 to 70 per cent of women who begin using OCs are still using them after one year. 22 , 26 This very high attrition rate might contribute to the overall failure rate when women discontinue OCs and fail to begin an alternative birth control method. Most women discontinue the pill for reasons of adverse symptomatology, not for reasons of serious complications or side effects. Hence, it is recommended that every woman receiving an OC be provided a second method of birth control, instructed in its use, and encouraged to practice using it. Types of Oral Contraceptives Initially, OC preparations contained a fixed-dose combination of estrogen and progestin. Monophasic oral contraceptives, first available in the 1960s, are still broadly used. As the role of the hormonal contents of oral contraceptives became better understood, some OCs were modified to deliver hormones in varying amounts to conform to the peaks in steroid production occurring naturally during the menstrual cycle. 14 The biphasic pill was introduced in 1982 as Ortho-Novum 10-11. To approximate physiologic hormone levels more closely, this pill delivers 0.5 mg norethindrone for the first 10 days and 1.0 mg for the final 11 days of the menstrual cycle. The decrease in progestin-to-estrogen ratio for the first half of the cycle should allow endometrial proliferation, and the increased ratio during the second half of the menstrual cycle should allow secretory development. In theory the incidence of breakthrough bleeding and midcycle spotting would be reduced; however, reports indicate these problems may still occur with biphasic oral contraceptives. Triphasic oral contraceptives, introduced in 1984, contain fixed or variable estrogen and variable progestin content. Triphasics were designed to reduce total progestin intake levels below those delivered by low-dose monophasic oral contraceptives. Potential progestin effects (e.g., increased blood pressure, increased lipid levels, and alterations in carbohydrate metabolism) are therefore minimized. Decreased midcycle breakthrough bleeding also has been reported. Patient

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and physician acceptance appear to be enhanced by the new approach employed in triphasic preparations. Currently available triphasics include the first triphasic preparation, Ortho-N ovum 7-7-7, which provides 35 I-Lg ethinylestradiol for all 21 tablets of the cycle and three levels of progestin dose. Norethindrone content is 0.5 mg for the first 7 days, increases to 0.75 mg for the next 7 days, and finally advances to 1.0 mg for the remaining 7 days of the cycle to provide endometrial support. Two other multiphasic oral contraceptives were subsequently made available. Tri-Norinyl contains a fixed estrogen dose of 35 I-Lg ethinyl estradiol and 0.5 mg, 1.0 mg, and 0.5 mg norethindrone content for 7, 9, and 5 days of the cycle period. Triphasil varies both estrogen and progestin content at days 1 to 6, 7 to 11, and 12 to 21. Studies indicate a use effectiveness rate of 0.33 pregnancies per 100 women-years and minimal blood pressure, weight, lipid, and carbohydrate metabolism changes. 56 Based on the relatively high estrogen-to-progestin ratio in triphasics, certain side effects have been reported. Fluid retention and breast tenderness can occur. Menstrual bleeding might seem excessive because of greater endometrial development. Incidents of late-cycle bleeding or spotting might become more frequent or heavier when compared with monophasic oral contraceptives. Wyeth reported a 180 per cent increase in spotting with Triphasil as compared with Ovral. 23 Ellis, however, observed no appreciable increase in breakthrough bleeding or quantity of flow when comparing Triphasil to higher dose, monophasic preparations. 14 Ortho-Novum and Ortho-N ovum 7-7-7 have almost equal incidences of breakthrough bleeding. The long-term use of multiphasic oral contraceptives requires further study; however, most current reports suggest that the risk of breakthrough bleeding in multiphasic oral contraceptives is equal to or slightly greater than the low-dose monophasic pills. 13. 18. 21. 56

CLINICAL APPLICATION OF HORMONAL CONTRACEPTION Patient Selection In choosing hormonal contraception as a primary method of birth control for the adolescent, the physician should observe evidence of a mature hypothalamic-pituitary-ovarian axis without physical or psychologic pathology. The individual patient should exhibit the following characteristics 49 : frequent sexual activity two to five times a week or more than six times a month, and poor compliance with other methods, and desire for maximal, immediate protection. The following are absolute contraindications for OC use documented by the FDA: thromboembolic disorder (or history thereof), cerebrovascular accident (or history thereof), breast cancer, estrogen-dependent neoplasm, pregnancy, undiagnosed abnormal vaginal bleeding, or known impairment in liver function. The many relative contraindications for OC use must be considered specifically for each patient, weighing potential risks against desired effects. These include patient due for surgery within the next 4 weeks; family

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history of seizures, diabetes, embolic phenomena, metabolic disease; severe headaches, especially vascular or migraine; severe hypertension; adult maturity not reached (i. e., absence of regular periods for 12 to 18 months); sickle cell disease; prolonged bed rest (e.g., long-leg cast); hepatic, pancreatic, renal, cardiac, or neurologic organ system dysfunction; psychiatric illness, especially depression; conditions predisposing patients to unreliability in following OC instructions (e.g., mental retardation, history of past poor medical compliance, strong ambivalance to contraceptive method, substance abuse); or concurrent use of rifampin unless patient is willing to use another backup method.

MANAGEMENT GUIDELINES 1. There should be evidence of a mature hypothalamic-pituitary-ovarian axis without physical or psychologic pathology. 2. If the adolescent has not exhibited 12 to 18 months of regular periods but is already having regular intercourse, the risk of pregnancy probably outweighs the risks of hormonal contraception. 3. The patient should have a detailed history and physical examination to rule out contraindications for usage. 4. Complete blood count, liver function tests, cholesterol, and fasting glucose test should be performed before patient begins taking oral contraceptives. If this is not possible, a complete blood count and urinalysis and a detailed history and physical are adequate. 5. Height, weight, and blood pressure should be measured and a pelvic examination with Pap smear should be performed initially and at 6 and 12 months unless more frequently indicated by irregular results. 6. Careful oral and written instructions on how to take the pill must be provided initially and reviewed at each patient visit. Memory is aided by the use of a 28-day package, paralleling the days of the week. 7. Patient should be followed at a minimum of 1, 3, 6, and 12 months during the first year. The danger signs of oral contraceptive use should be reviewed at each visit. These have been listed in mnemonic fashion by Hatcher as follows: Early pill danger signs: A - Abdominal Pain (Severe) C - Chest Pain (Severe) (cough, shortness of breath) H - Headaches E - Eye Problems (Visual loss or blurring) S - Severe leg pain (calf or thigh) 8. A backup method, such as foam or condom, should always be used with each coital episode for the first month of pill taking. 9. Use of a condom should be encouraged in addition to oral contraception in situations of multiple partners, sexually transmitted diseases, intravenous drug use in partner or uncertain sexual history of partner. 10. The possibility of minor side effects (e.g., breakthrough bleeding, nausea) must be addressed at each visit. These complaints must be addressed regularly to enhance compliance. 11. A lower estrogen pill (30--50 J.Lg) should be used in this age group.

The individual clinical situation may necessitate alterations in the choice of a specific agent. It is our belief that pharmacologic agents should be used at the smallest possible dosages to achieve the desired effects. For

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most young healthy women, a low-dose combined OC with 30 to 35 /-Lg ethinyl estradiol is the logical first choice. It is important to anticipate and describe to the patient the higher likelihood of spotting, breakthrough bleeding, and missed menses associated with low-dose OCs. These complications often lead to pill discontinuation especially in the adolescent user, and therefore must be addressed regularly. The differences in safety among the low-dose estrogen preparations are as yet unclear; therefore, choosing among the various products might be based on differences of progestin dose and androgenicity. Nordette and Lo-Ovral contain norgestrel, the most androgenic progestin. Increased androgenicity can be useful in managing women with complications of spotting or amenorrhea while using other low-dose OCs. Additionally, cases of dysfunctional uterine bleeding have been managed successfully using norgestrel-containing OCs. Preparations containing norgestrel might be helpful in managing leukorrhea, fluid retention, and exacerbations of fibrocystic disease. The preparation with the least androgenicity is Ovcon-35, containing 0.4 mg norethindrone. Modicon and Brevicon each contain 0.5 mg of norethindrone. These preparations might be indicated for patients with acne, or when the oral contraceptive is used to suppress androgenic traits (i.e., hirsutism). A preparation with increased androgenicity is desirable in managing the complaint of noncylic weight gain associated with increased appetite during pill use. Ovcon-35 also possesses the least progestin effects. It is therefore associated with minimal lipid changes and hypertensive effect. This preparation is recommended for patients with hypertension or diabetes mellitus who have a strong desire for OC therapy. This preparation is indicated also for the patient who smokes and insists on using hormonal contraception as her primary method of birth control. Table 1 summarizes the hormonal side effects of oral contraceptives. Risk-Benefit Concept The earliest retrospective investigations of OC risks were reported in the late 1960s. Over the following 20 years with improved formulation of OCs, evidence indicates a very favorable benefit-to-risk ratio regarding OC use in the adolescent population less than 25 years old. Only recently have the major health as well as social benefits been noted. These benefits have perSisted in spite of the significant reduction in steroid dosage. OC use is safer than pregnancy and delivery in women under age 35. In this group, the risk of death from all methods of birth control is lower now than from unintended pregnancy and childbirth. 37 Tables 2 and 3 present a review of risks and benefits associated with OC adolescent use. The tables are patterned after those created by Smith and Youngkin. 50 Side Effects Commonly occurring side effects of OCs have been evaluated in previous literature. The following guidelines for managing OC side effects have been derived from current literature and our clinical experience. Nausea, Vomiting, and Abdominal Pain. Higher estrogen-dose preparations (50 /-Lg) are more associated with nausea and vomiting than are low-

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Table 1. Hormonal Side Effects of Oral Contraceptives ESTROGEN EXCESS

Nausea, vomiting Edema bloating Cyclic weight gain Dysmenorrhea, uterine cramps Breast tenderness, increased breast size, vascular headaches Chloasma Lactation suppression Irritability, depression

PROGESTIN EXCESS

Fatigue, depression Acne, oily skin, hirsutism

ESTROGEN DEFICIENCY

Irritability, nervousness Hot Hashes, motor symptoms

PROGESTIN DEFICIENCY

Late breakthrough bleeding and spotting

Alopecia Early midcycle spotting Heavy menstrual How and clots Increased appetite, shortened menses Delayed onset of menses, Decreased amount of early menstrual dysmenorrhea, weight loss Decreased libido How No withdrawal bleeding Headaches between pill packages Dilated leg veins Cholestatic jaundice

Dry vaginal mucosa, atrophic vaginitis Headaches Depression

Adaptedfrom Dickey RP: Medical approaches to reproductive regulation: The pill. In Managing Contraceptive Pill Patients, Ed 4. Oklahoma, Creative Informatics, Inc, 1984.

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Table 2. Risks to Adolescents from Oral Contraceptives CONDITION OR DISEASE

Myocardial infarction

Thromboembolic stroke

Subarachnoid hemorrhage Deep venous thrombosis

Hypertension

Lipid levels

Blood glucose

Cervical cancer

Breast cancer

Liver tumors

Other

FINDINGS

Risks minimal in young healthy, nonsmoking women 8 Risk increases in smokers after age 3748 No deaths from MI associated with OC use in women 25 years old 9, 18 Two deaths from MI per 100,000 women per year in pill users 20 to 29 years old l5 Risks increases when over 35 years and in the presence of diabetes, hyperlipidemia, obesity, and AB blood type43 Risk higher in OC users.' 13, 18 Smoking increases risk synergistically' Hypertension increases stroke risk' Increased risk in women 35 years of agel, 4, 5 Smoking and HTN increase risk Relative risk of 4 cases per 100,000 users per year52 Minimal risk with low-dose OC use 12 Grossly inaccurate diagnostic rates of DVT overestimating incidence and causality18 OC should be discontinued 4 weeks prior to surgery to avoid thromboembolic complications" Overall risk of developing hypertension is two to three times that of nonuser Risk related to advancing ageS Progestin implicated as causative agent9 No blood pressure change with triphasic use56 No causal association between low-dose OC use and hypertension3 Usually quickly reversible 22 HDL levels lowest in high-potency progestin users 28 Risk related to advancing ageS Triglyceride levels rise approximately 10% with OC use4 Minimal lipid changes with triphasic preparation56 Lipid-level changes minimal with low-dose OCS, 13, 17 Higher LDL-to-HDL ratio, higher cholesterol levels in nonphysically active black OC users, ages 16 to 28 years2• Overall effect of OC use minimal on glucose tolerance l3, 57 No increased risk for diabetes mellitus in normal women27 Higher progestin potency might lower insulin binding27 Woman using OC for 4 to 6 years showed relative risk of 1.6 to 3.4 times depending on sexual activity leveI8,53 Risk of neoplasia associated with duration of use25 No causal relationship established lO, 18,45 No increased risk in any subgroup in women less than 25 years old3l Earlier studies linked cancer development in nulliparous women with high-progestin dose OC24, 30 Incidence of benign liver tumors 0.4 per 100,000 in nonusers or short-term users; 3.4 per 100,000 in long-term users (more than 2 years)50 Risk increased with dose of steroid and age of users Mortality approximately 3 per million long-term users per year due to secondary hemorrhage l5 No increase in incidence of melanomal5 , IS, 24 No increase in pituitary adenomas l5, 18 No deleterious effects on hearing'" Incidence of gall bladder disease increased during first 4 years of OC use; evidence of continuing effectl5 , 44 Liver diseases (e,g" Gilbert's, Rotor's syndrome, active hepatitis, prophyria) might be exacerbated by OC use l5, 44 No premature closure of epiphyses; nO limitation on attainable height22, 2.

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Table 3. Benefits Associated with Oral Contraceptives CONDITIONS OR DISEASE

Morbidity with mortality associated with pregnancy

Hospitalizations Abortions Pelvic inflammatory disease

Ectopic pregnancy

Pregnancy and infant casualty Return of fecundity Predictability of cycle Premenstrual syndrome Dysmenorrhea Ovarian cancer

Functional ovarian cysts Endometrial cancer

Iron deficiency anemia

Rheumatoid arthritis

FINDINGS

Reduced risk of anemia, malnutrition, decreased immune response associated with pregnancy" 15 Seven of 100,000 women 25 years old die of unintended pregnancy; fewer than 1 per 100,000 women 25 years old die of OC-associated complications l2· 37 Estimated that OC use will prevent 50,000 hospitalizations in United States 37. 50 Estimated that OC use will prevent 1 to 7 million abortion requests annually worldwide50 Pill users are 35 to 50% less likely to develop PID than nonusers15, 38, 39, 41 Lower-tract infections (e.g., Chlamydia trachomatis infection) might be increased55 Lower incidence secondary to reduced PID, reduced ovulation 12, 23, 39, 41 Estimated more than 10,000 hospitalizations secondary to ectopic pregnancy averted annually9,37 No increase in spontaneous abortion, birth defects, or infant mortality reported with low-dose OC use 1, 15 Pregnancy achieved by 42 months after discontinuance of OC, average 30 months23 Onset of menses predictable in 78% of cycles, similar in triphasic OC use36 Improvement in premenstrual syndrome (PMS symptoms )1, 15, 23 Decreased complaints of pain symptoms15,50 30% to 60% relative risk reduction related to duration of use; protection might persist for 10 to 15 years; 1000 total deaths averted15, 18, 50 Decreased risk of developing cysts l2, 25, 37, 50 A 50% to 60% relative risk related to duration of use; protection might persist for 5 years l5, 18, 22, 50 2000 cases estimated prevented by long-term OC use each year23 Normal iron values more probable, 50% decreased menstrual flow reduces need for dilation and curettage procedure for dysfunctional uterine bleeding1, 15, 33 50% decline in risk with OC use41 , 50

dose OCs. These symptoms usually occur early in therapy and diminish within 3 months of OC use. Before attributing nausea to OC use, the clinician must first rule out intrauterine or ectopic pregnancy, and also consider the possibility of gall bladder disease, gastroenteritis, mononucleosis, or infectious process. Guidelines for management of nausea and vomiting are as follows: 1. The OC can be taken with the evening meal or at bedtime so that the peak concentration occurs during sleep. 2. Inform the patient that nausea often decreases as a problem after the first few cycles. 3. If nausea persists beyond a third cycle of the therapy, use a lower estrogen/ greater progestin OC preparation. 4. If vomiting occurs within 2 hours of taking the pill, the efficacy will decrease.

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The dose should be repeated and an additional method of birth control prescribed. If vomiting and diarrhea persist during this cycle, the patient should be advised to use an additional method of birth control.

Headache Headache is a common OC side effect and can be caused by either estrogen or progestin. Headache is a symptom that must be taken seriously because it is a major danger signal that precedes a cerebral vascular accident. In evaluating the patient complaining of headaches, the clinician must consider many conditions: migraine headaches, vascular headaches, cerebrovascular accident, hypertension, fluid-retention-associated headache, nervous system tumor, and infectious conditions. Social concerns and functional disorders are also among the differential diagnoses for headache in the OC user. Guidelines for managing headache are as follows: 1. Rule out the presence of concomitant serious disease. 2. If the headache is clearly related to initiation of OCs, the pill should be discontinued or changed to a preparation with lower estrogen or lower progestin activity. 3. The patient must be seen again regularly within one or two cycles. 4. The clinician must take headaches in the OC user seriously because they are a major danger signal.

Weight Gain Weight may increase, decrease, or remain the same with OC use. Estrogen excess is usually manifest by weight gain associated with fluid retention (cyclic weight gain), whereas acyclic weight gain usually is related to progestin-induced appetite increase. Guidelines for weight gain management are as follows: . 1. Monitor calorie intake; increase activity. 2. For acyclic weight gain, change to a lower-progestin OC. 3. For cyclic weight gain, switch to a lower-estrogen preparation.

Acne Acne that worsens during OC use can be exacerbated by a highly androgenic OC preparation, high endogenous ovarian or adrenal estrogen production, or coexisting dietary and familial factors. Guidelines for management include the following: 1. Switch to a low-androgen pill. 2. Suggest alternative approaches to treatment of acne, including broadspectrum topical and systemic antibiotic, dietary changes, soaps and cleansers, and specific antiacne medicine. 3. It is imperative that women taking Accutane use a reliable contraceptive. Accutane use in early pregnancy has an almost 100 per cent incidence of severe neurologic defects in the fetus. Contraception should continue for at least 30 days after Accutane is discontinued. 4. Refer patient to a dermatologist or endocrinologist for further evaluation.

Breast Effects Breast discomfort, breast tenderness, or breast fullness can be related to the OC estrogen component. In considering the complaint of breast

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tenderness, the clinician must entertain the possibilities of actual growth of breast tissue during normal adolescence, early pregnancy, masses, or tenderness from fibrocystic disease, or breast cancer. After ruling out the possibilities of pregnancy and breast cancer, guidelines are as follows: 1. Switch to an OC that has less estrogen. Breast tenderness might be an indication for a 20-f.Lg pill. 2. Elimination of methylated xanthines has benefited some symptomatic women, as has the avoidance of vigorous exercise during times of discomfort.

Breakthrough Bleeding One of the most common and adverse side effects of OCs is breakthrough bleeding, which can occur early in the first month of use; however, it also can occur after the woman has been taking the pill for several months. Early bleeding resolves itself in half of women within three cycles. Bleeding that occurs early in cycle represents lack of estrogen stimulation, whereas bleeding after midcycle indicates a progestin deficiency. The differential diagnosis for breakthrough bleeding includes threatened or spontaneous abortion, ectopic pregnancy, pelvic inflammatory disease, endometriosis, cervical or endometrial cancer, and missing or altering the time of taking the OC. In managing breakthrough bleeding, the clinician must do the following: 1. Rule out pathologic causes. 2. Confirm that OCs are taken at the same time each day and that no doses have been missed. 3. Allow four cycles for the patient to adjust to the OC. Breakthrough bleeding decreases dramatically over the first 4 months of pill use. The patient must be reassured and educated at the onset of therapy about the possibility of breakthrough bleeding. 4. In the instance of early-cycle breakthrough bleeding, switch to an estrogen pill. A short course of conjugated estrogen (Premarin) can be given along with the current OC on days 1 to 7 of the cycle rather than switching the cycles completely. 5. For late-cycle breakthrough bleeding,/switch to a higher progestin pill. 6. If bleeding is not stopped, discontinue the OC use and reevaluate the possible causes. Another method of birth control should be prescribed. 7. Advise the patient with persistent breakthrough bleeding not to use tampons continuously because of the increased risk of toxic shock syndrome.

Absence or Withdrawal of Bleeding Amenorrhea is a common side effect, especially in those patients taking low-dose OCs. The symptom occurs because of the suppressive effect of continuous progestin on endometrial proliferation. The absence of withdrawal bleeding is most commonly encountered during the first two cycles of OC use: however, it can occur throughout the course of therapy. Guidelines for evaluation of amenorrhea include the following: 1. Rule out the possibility of pregnancy with a sensitive HCG test. 2. Stop the OC if pregnancy is suspected. The patient should use a barrier method of contraception until pregnancy is definitely confirmed or ruled out. 3. Reassure the woman that the problem is usually not harmful. 4. Prescribe higher-estrogen OC.

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Depression Depression as a symptom of OC use has been reported in 5 to 30 per cent of users. Related symptoms include irritability, lethargy, decreased libido, emotional instability, and sleep disturbances. Depression is more common in women with preexisting episodes of depression or premenstrual syndrome. OC use does not appear to increase the risk of neurosis nor has its use been associated with alterations in the Minnesota Multiphasic Personality Inventory Test. Depression, lethargy, and tiredness can be related to the progestin in the pill. An estrogen deficiency can also be implicated in depression. There is some evidence that vitamin Bs (pyridoxine) decreases secondary to OC use and therefore can contribute to endogenous depression. Suggested guidelines for management of depression are: 1. If depression is severe, the patient should be referred for psychiatric help. 2. Rule out other physiologic or pathologic causes of the symptom (e.g., thyroid disease, hormonal deficiency, or pregnancy). 3. Depression is most likely caused by progestin excess; consequently, a decrease in the progestin or an increase in the estrogen component of the OC might be useful. 4. Pyridoxine (25-50 mg per day) can be given as an additional therapeutic modality. 5. If depression is clearly related to OC use, the pill should be discontinued and an alternative method of contraception prescribed.

Interactions with other medications being taken can reduce the effectiveness of OC agents. Therefore, the physician must document all medications that the adolescent is taking and advise her that she should check with the physician before using other medications while taking the pill. Table 4 lists drugs commonly implicated in OC drug interactions.

MINIPILLS

The minipill was introduced in 1973 as an alternative to the combined OC to eliminate estrogen-related side effects. These pills contain a smaller dose of the progestin included in OCs, with no estrogen component. MicroNor (Ortho) and Nor-Q-D (Syntex) contain 35 mg of norethindrone, which is slightly less than the amount contained in Ovcon-35, the lowest norethindrone-containing combined pill. Ovrette (Wyeth) includes 0.075 mg of norgestrel per pill. In theory, minipills should be safer OCs because many of the classical pills' major and minor side effects are estrogen related (e.g., cardiovascular risks). Studies of actual comparative use are not available. Use of minipills has not gained wide popularity, probably because of poor bleeding control. 13 Irregular menses, spotting, and decreased menstrual flow are reported by users. Adolescent compliance is especially negatively affected by breakthrough bleeding and unpredictability of periods. 14. 21 Progestin-related side effects of hirsutism, edema, weight gain, and alterations in liver function are reported. 22 The effectiveness rate of minipills is less than that of OCs. It is reported that 40 per cent of users have regular

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Table 4. Drugs Implicated in Oral Contraceptive Drug Reactions CLASS OF COMPOUND

DRUG

Anticonvulsant

Barbiturates; phenobarbital, carbamazepin, phenytoin, ethosuximide

Cholesterol-lowering agent

Clofibrate

Antibiotics'

Rifumpin, Isoniazid, Penicillin, Ampicillin, Metronidazole, Tetracycline, Neomycin, Chloramphenicol, Sulfonamide, Nitrofurantoin Benzodiazepines, Barbiturates, Chloral hydrate, Antimigrane preparations

Sedatives and hypnotics

Antacids

All

PROPOSED METHOD OF ACTION

Induction of liver microsomal enzymes, rapid metabolism of estrogen; and increased binding of progestin, ethinyl, and estradial to sex hormone binding globulin. Reduces elevated serum triglycerides and cholesterol, reduces OC efficacy Rifampin increases metabolism of progestins. Enterohepatic circulation disturbance. Induction of microsomal liver enzymes Increased microsomal liver enzymes

Decreased intestinal absorption of progestins

SUGGESTED MANAGEMENT

Use another method, another drug, or higher dose OCs

Use another method For short course, use additional method or use another drug For long course, use another method

For \;hort course, use additional method or another drug; for long course, use another method or high-dose OC Use additional method

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ovulatory cycles and 20 per cent variable ovulatory and anovulatory cycles. 23 Manufacturers claim failure rates of 3.75 pregnancies per 100 women-years in new, first-time minipill users. A failure rate of 1. 95 is shown in patients who switch from an OC to a minipill. Pregnancy rates are highest during the first 6 months of use, so it is advisable to encourage a second method of contraception during midcycle in early minipill therapy. Minipill use is indicated in the patient who has shown excessive estrogen-related side effects (e.g., headaches, hypertension, varicose veins, leg pain, nausea, and chloasma) and a history of increased cardiovascular risk. Weight gain and depression might be estrogen or progestin related and should be evaluated individually. Women 35 years and over are better suited for minipill use. Physicians should consider minipill as a method of contraception for adolescents only in those with specific medical conditions, and in whom estrogen may exacerbate the underlying process. A progestin-only minipill is the desirable choice for the lactating mother who wants oral contraception without diminished milk production. In addition to nonimpairment of lactation, the severity of dysmenorrhea and total menstrual blood loss is lessened with minipill use. Another noncontraceptive benefit attributed to minipills is decreased incidence of pelvic inflammatory disease. Progestin-induced, thick, sticky, cervical mucus impairs sperm ascent and also may impair internal seeding by gonococcus. Absolute contraindications for minipill use are the same as those for the OC. Because of the increased frequency of irregular bleeding with the minipill, unexplained abnormal uterine bleeding must be seen as an absolute contraindication that requires complete evaluation. Women with irregular bleeding patterns, history of ectopic pregnancy, and acute mononucleosis are not desirable candidates. Administration instructions and followup care are the same for OC use. It should be emphasized that the user read the package insert and start taking her pill at the first day of menstrual bleeding. Mood, libido changes, and depression, as well as the pill danger signs, should be reported to the clinician. A backup method might be used midcycle to improve pill effectiveness. Progestin effects of breakthrough bleeding, spotting, and irregular or infrequent periods should be anticipated and discussed with the patient.

OTHER HORMONAL CONTRACEPTIVE METHODS Mechanisms for delivering long-acting progestins include depot injections, hormone-elaborating implants, medicated vaginal devices, and progestin-releasing IUDs. These methods are currently employed in at least 80 countries and have been studied in at least 5 million women but have limited use in the adolescent population.!3 Medroxyprogesterone acetate (Depo-Provera) or DMPA is the most common injectable contraceptive. It has been used worldwide for over 10 years. FDA disapproved the preparation in 1978 for reasons of possible teratogenicity, development of breast tumors in beagles, abnormal bleeding patterns, and no real need for such a contraceptive in this country. Sub-

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sequent studies and evaluations have not confirmed the FDA's fears: rather, in 1982 The World Health Organization (WHO) reported that 15 years of use demonstrated no additional and possibly fewer adverse side effects than are found in other methods of hormonal contraception. 12 The study showed the DMPA can exert a protective effect with a reduced rate of breast cancer. Epidemiologic evidence might contribute to injectable progestin use in this country. Distinct advantages of the injectable contraceptive include its long duration of action and high rate of effectiveness. The standard dose of DMPA (150 mg intramuscularly every :J months) yielded a pregnancy rate of 0.4 pregnancies per 100 women-years. 13 Other long-acting injectable progestins currently are used by over half a million women; given at 84day intervals, a pregnancy rate of 1.4 per 100 women-years is reported. 12 Other long-acting injectable preparations, given at 2- to 3-month intervals, are being evaluated. Combined estrogen and progestin injections are being developed to reduce bleeding irregularities and allow for monthly menstruation. The primary reason for discontinuance of injectables is irregular bleeding, thereby placing the priority of development on monthly combined injectables. Ongoing studies continue to evaluate possible cardiovascular and neoplastic risks. Another development in contraceptive technology is the subdermal implantation of slow-releasing capsules or rods containing progestin. The levonorgestrel Norplant subdermal implant system consists of six 2.4 cm X 3.4 mm subdermal capsules that release levonorgestrel over 6 to 7 years. The devices are inserted subdermally, usually in the inner aspect of the upper arm or palmer aspect of the forearm. This is the only implantable system available for large-scale use in family programs and was developed by the Population Council in 1983. 42 Levonorgestrel shows a slow rate of release, approximately 80 mg per day during the first 6 to 18 months of use to an average of 30 mg per day over 5 years. WHO reported the pregnancy rate of 2.6 per 100 women-years. The safety of Norplant has been assessed favorably, as has DMPA and norethisterone enathate, and a high continuation rate of 89 per 100 women after 4 years also has been recorded. Other advantages include increased hemoglobin levels during use and decreased menstrual blood loss. The incidence of ectopic pregnancy was less than that associated with minipill or progestin IUD use. Other implant systems have been developed using mechanisms of single-hormone release capsules, subcutaneous bioabsorbable pellets, and injectable pellets. Technologic advances anticipate insertion by injection, simple retrieval available during active life, and biodegradable compounds after exhaustion of the drugs. Vaginal rings have been developed over the past 10 years as an alternative method of hormonal contraceptive. These intravaginal, ringshaped devices are worn like a diaphragm; however, they exhibit no barrier effect. Contraception is achieved by slow, continuous release of steroids over an extended period. Two types of vaginal rings exist: continuous-use type with progestin that lasts over 3 months and are not removed during menstruation, and discontinuous types that are removed during menses and use larger steroid doses. Vaginal rings can be removed during inter-

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course and replaced afterward. The effectiveness of vaginal rings was observed to be 3.6 pregnancies per 100 women-years in a 13-country clinical trial. 22 The advantages of the system include effective contraception, self-administration, ready reversibility, and enhanced absorption of progestin locally and systemically unimpeded by any first-pass effect by the liver. Pending further studies, vaginal-ring use might become a practical alternative to OC use in responsible adolescents. Levonorgestrel and progesterone-elaborating IUDs are being developed and studied by WHO. They release just 20 mg of levonorgestrel per day for 3 to 5 years and yield a 4 per cent pregnancy rate. Significant reduction of menstrual blood loss is noted, with good relief of dysmenorrhea. Ectopic pregnancy rate did not increase, however, amenorrhea led over 10 per cent of users to request removal of the device. Progestasert is the only hormonal IUD available today. This device delivers 65 fJ.g progesterone per day and has an active life span of 1 year. The safety of IUD use remains controversial, and we therefore do not recommend their use in the adolescent patient at this time. The technology of hormonal contraception continues to evolve, providing safer and more practical avenues of contraception. Understanding gained over the past 25 years has resulted in safe OC preparations appropriate for use by the sexually active adolescent. The prevalence of sexual activity in pregnancy among adolescent women requires that the clinician understand the concepts and applications of hormonal contraception, and that he or she provide careful, individualized prescription of hormonal contraception.

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15. Fraser IS: A health perspective of hormonal contraceptives. Acta Obstet Gynecol Scand (Suppl) 134:33-43, 1986 16. Gallup Organization: Attitudes toward contraception. Princeton, N.J., March 1, 1985. 17. Gaspard UJ: Metabolic effects of oral contraceptives. Obstet Gynecol 157:1029-1041, 1987 18. Goldzieher JW: Hormonal contraception: Benefits versus risk. AMJ Obstet Gynecol 157:1023-1028, 1987 19. Greenblatt RB: Oral contraceptives: The state of the art. Clin Therap 8:6-23, 1985 20. Green GR, Sartwell PE: Oral contraceptive in patients with thromboembolism following surgery, trauma or infection. Am J Public Health 62:680, 1972 21. Hale RW: Phasic approach to oral contraceptives. Am J Obstet Gynecol 157:1052-1058, 1987 22. Hatcher RA, Guest F, Stewart F et al: Contraceptive Technology. Ed 13. New York, Irving Publishers, 1986 23. Helmrich SP, Rosenberg L, Kaufman DW et al: Lack of an elevated risk of malignant melanoma in relation to oral contraceptive use. JNCI 72:617-620, 1984 24. Henderson BE, Krailow MD, Pike MC et al: Breast cancer in young women and use of oral contraceptives: Possible modifYing effect of formulation and age of use. Lancet 2:926-930, 1983 25. Huggins GR, Zucker PK: Oral contraceptives and neoplasia: 1987 update. Fertil Steril 47:733, 1987 26. Jay MS, Bridges CE, Gottlieb AA et al: Adolescent contraception: An overview. Adolesc Pediatr Gynecol 1:83-95, 1988 27. Kalkhoff RK: Effects of oral contraceptive on carbohydrate metabolism. J Steroid Biochem 6(6):949-956, 1975 28. Knopp RH, Walden CE, Whal PW et al: Oral contraceptive and postmenopausal estrogen effects on lipoprotein, triglyceride and cholesterol in an adult female population: Relationships to estrogen and progestin potency. J Clin Endocrinol Metab 53:11231132, 1981 29. Linder CW, DuRant RH, Jay S et al: The influence of oral contraceptives and habitual physical activity on serum lipids in black adolescents and young women. Section of General Pediatrics and Adolescent Medicine, Dept. of Pediatrics, Medical College of Georgia. 30. McPherson K, Neil A, Vessey MP et al (letter): Oral contraception and breast cancer. Lancet 2:1414-1415, 1983 31. Miller DR, Rosenberg L, Kaufman DW et al: Breast cancer risk in relation to early oral contraceptive use. Obstet Gynecol 68:863, 1986 32. Neel EU, Litt IF, Jay S: Side effects and compliance with low- and conventional-dose oral contraceptives among adolescents. Adolesc Health Care 8:327-329, 1987 33. Neinstein LS, Katz B: Contraceptive use in the chronically ill adolescent female. Part II. Adolesc Health Care 7:350-360, 1986 34. O'Reilly KR, Aral SO: Adolescence and sexual behavior. J Adolesc Health Health Care 2:43-51, 1988 35. Orme LE, Back DJ: Interactions between oral contraceptive steroids and broad-spectrum antibiotics. Clin Exper Dermatol 11:327-331, 1986 36. Ortho Pharmaceutical, Medical Services Dept: Summary of clinical evaluation of OrthoNovum, 10/11, Aug 1982 37. Ory HW, Forrest JD, Lincoln R et al: Making choices: evaluating the health risks and benefits of birth control methods. New York, Alan Guttmacher Institute, 1983 38. Ory HW: The noncontraceptive health benefits from oral contraceptive use. Family Plann Perspect 14:182-184, 1982 39. Ory HW: The noncontraceptive health benefits from oral contraceptive use. Family Plann Perspect 14(4):182-184, 1982 40. Piper JM, Kennedy DL: Oral contraceptive in the U.S.: trends in content ad potency. Int J Epidemiol 2:215-219, 1987 41. Population Reports: Oral contraceptives. 10(3):A189-A222, 1982 42. Population Reports(A) No 6: Oral contraceptives in the 80s. 1982 43. Rosenberg L, Kaufman DW, Helmrich SP et al: Myocardial infarction and cigarette smoking in women younger than 50 years of age. JAMA 253:2965-2969, 1985

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44. Royal College of General Practitioners' Oral contraception study.: Oral contraception and gall bladder disease. London, Pitman Medical, 1974 45. Rubin GL, Peterson HB: Oral contraceptive use and cancer. Contraceptive Technology Update, Jan. 1985 46. Samani F, Bolzonello P, Fior R et al: Effects on hearing during prolonged oral contraceptive use. Contraception 35:41, 1987 47. Senanayake PL, Kramer D: Contraceptive and the etiology of pelvic inflam. disease: New perspectives. Am J Obstet Gynecol 138:852, 1980 48. Shapiro S, Sloan D, Rosenberg L et al: Oral contraceptive use in relation to myocardial infraction. Lancet 1:743-747, 1979 49. Shearin RB: Adolescent Sexuality and Gynecology. Ed 2, Norwalk, Connecticut, Appleton and Lange, 1989 50. Smith MA, Youngkin EQ: Current perspectives on combination oral contraceptives. Clin Pharm 3:485-495, 1984 51. Stadel BV: Oral contraceptives and cardiovascular disease. N Engl J Med 305:672-677, 1981 52. Stadel BV: Oral contraceptives and cardiovascular disease (pt. 1). N Engl J Med 305:612618, 1981 53. Swan SH, Brown WL: Oral contraceptive use, sexual activity and cervical carcinoma. Am JObstet GynecoI139:52-57, 1981 54. Wahl P, Walden C, Knopp R et al: Effect on estrogen/progesterone potency on lipid! lipoprotein cholesterol. N Engl J Med 308:862-867, 1983 55. Washington AE, Gora S, Schacter J et al: Oral contraceptives, Chlamydia trachomatis infection and pelvic inflammatory disease. JAM A 253:2246-2260, 1985 56. Woufersz TB, Butler AJ, Cohen M: A low-dose triphasic oral contraceptive. Fertil Steril 47:425, 1987 57. Wynn V, Adams PW, Godsland J et al: Comparison of effects of different combined oral contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1:1045-1049, 1979 Division of Adolescent Medicine Georgetown University 3800 Reservoir Road, NW Washington, D.C. 20007