lnt
J Gynaecol Obstet
16: 547- 555, 1979
Initial Pill Selection and Managing the Contraceptive Pill Patient Richard P. Dickey Department of Obstetrics and Gynecology, Louisiana State University College of Medicine, New Orleans, Louisiana, USA
ABSTRACT Dickey RP (Dept of Obstetrics and Gynecology, Louisiana State University College of Medicine, New Orleans, LA, USA). Initial pill selection and managing the contraceptive pill patient. lnt} Gynaecol Obstet 16: 547- 555, 1979 Contraceptive pill risk may be lowered and patient continuation rates increased by selecting a pill best suited to each patient's needs. Each contraceptive pill has a unique profile of activity which is dependent upon both the dosage and type of progestogen and estrogen. Patient characteristics, especially menstrual history, are helpful in choosing an initial pill (which should be low in estrogen), and patient and family histories are also valuable in helping determine whether use of the pill is contraindicated. Patients with a history of sensitivity to their own hormones are more likely to experience side effects on contraceptive pills, as also are underweight women. Knowledge of individual pill activities and potencies can be helpful in selecting the initial pill and in changing pills when nonserious side effects occur.
INTRODUCTION Although the risk associated with contraceptive pill use is less than the . risk associated with pregnancy at most ages, this risk might be further lowered by selecting a pill best suited to individual patient needs and avoiding pill use entirely in those patients with particularly bad personal or family histories (4). Since all of the serious side effects associated with contraceptive pill use-with the possible exception of hypertension, altered glucose metabolism and depression-are related to estrogen content, the most promising method of reducing risk seems to be the selection of pills with very low estrogen content. As the estrogen content of contraceptive pills is lowered, first the incidence of menstrual cycle irregularity, spotting or staining, breakthrough bleeding and absence of bleeding between periods is increased ; and ultimately, there is some loss of effectiveness.
The progestational component of the pill becomes correspondingly more important for menstrual cycle control and for contraceptive effect iveness as the estrogen content is lowered. Certain progestins are more effective than others in controlling menstrualrelated events and in contraceptive effectiveness (Table I). These two characteristics of progestogens are associated with their androgen potency. Contraceptive pills differ considerably in both their dosage and their potency (5). Patient characteristics, such as usual menstrual pattern, weight and history of symptoms during the menstrual cycle or pregnancy associated with estrogen, androgen or progesterone, may be correlated with the occurrence of menstrual cycle and other side effects of contraceptive pill use, and may, therefore, influence the choice of a contraceptive pill. Selection of an initial contraceptive pill is concerned with differences both in pills and in patients. There are certain conditions which are absolute contraindications to contraceptive pill use. These are: l. Thrombophlebitis, thromboembolic disorders, cerebrovascular disease, myocardial infarction or coronary artery disease, or a past history of these conditions; \. 2. Markedly impaired liver function; 3. Known or suspected carcinoma of the breast; 4. Known or suspected estrogen-dependent neoplasm; 5. Undiagnosed abnormal genital bleeding; and 6. Known or suspected pregnancy. In addition, there are conditions which predispose patients to the risk of cardiovascular disease. These are: type II hyperlipidemia, diabetes mellitus, hypertension, previous hypertension of pregnancy, obesity and smoking. All of these are associated with an increased risk of myocardial infarction in oral contraceptive (OC) users. This risk also increases with age after age 30, with duration of use and with the estrogen dosage ( l) . Varicose veins of the legs and obesity increase the risk of thrombophlebitis. Other conditions are relative contraindications lntj Gynaecol Obstet 16
548
Dickey
Table I. Progestogen potency". Progestational Compound
b
Estrogenic
Delay of Menses
Subnuclear Vacuolization
Ventral Prostate
Vaginal Epitheliumb
Antiestrogenic
1.000
1 .00
7.6
0.00
18.5
0.500
0.53
1.0
0.86
1.0
0.067 0.050 0.036
0.45 0.38 0.13
2.5 1.6 0.0
0.38 0.25 2.08
25.0 2.5 0.0
Norgestrel Ethynodiol diacetate Norethindrone acetate Norethindrone Norethynodrel 8
Androgenic
Source: R. P. Dickey (5). Ethinyl estradiol = 100%.
because they may worsen during pill use; however, in other cases, they may actually improve during pill use. These include fibrocystic disease of the breast, asthma, epilepsy, migraine headaches, depression, leiomyoma of the uterus, ulcerative colitis and other conditions known to be affected by pregnancy (8). Finally, certain family histories suggest an mcreased risk of cardiovascular disease. The presence of myocardial infarction, cerebrothrombosis or hemorrhage (stroke) and pulmonary embolism in close relatives (mother, father, brother or sister) before the age of 50 indicates a possible familial tendency. It is recommended that, when this history is present, OCs should either not be used or should be used with caution after considering the age of onset and possible predisposing factors in the relative (4).
PILL CHARACTERISTICS The number of pills available for contraceptive use in the countries represented at this meeting are: Australia, 31; Canada, 28; France, 15; Sweden, 19; United Kingdom, 18; and USA, 29. When those which are duplicates differing in name only are removed, there remain 15- 24 different OC pill formulations available in each country. In Canada, where there are 21 different formulations, 12 of these contain 50 p.g or less of estrogen. In the USA, where there are 20 different formulations, 13 contain 50 p.g or less of estrogen. Although there are little or no differences in effectiveness among these pills, there are major differences in the occurrence of menstrual-related events, spotting or staining, breakthrough bleeding and missed menses and in the estrogenic, progesta-
lntj Gynaecol Obstel /6
tiona! and androgenic potency of the different contraceptive pills. These differences are due to both the dosage and the specific characteristic activity of the different progestogens and estrogens in the pills. Table I shows the comparative progestational, androgenic and estrogenic activities of the five progestogens used in Canada and the USA. Progestational activity is expressed relative to the most potent drug, norgestrel, and is shown as determined by two different methods (6). The delay of menses test, used for many years, has an inherent flaw since estrogenic and androgenic actions of the progestins, which also influence menstrual activity, can only be partly compensated for by adding fixed amounts of estrogen to the progestogen being tested. Thus, norgestrel, the most potent progestogen in the delay of menses test, appears to be 20 times more progestational than norethindrone. This means that the pill Ovral (Wyeth Laboratories, Philadelphia, PA, USA) must be ten times more progestational than Norinyl l/50 and 1/80 (Syntex Laboratories, Inc, Palo Alto, CA, USA) or Ortho-Novum 1/50 and 1/ 80 (Ortho Pharmaceutical Corp, Raritan, NJ, USA). But this clearly is not the case. The other progestational test, induction of subnuclear vacuolization, is influenced very little or not at all by the estrogenic and androgenic action of progestogens. According to the subnuclear vacuolization test, norgestrel is 2.6 times as progestational as norethindrone. This makes Ovral 30% more progestational than Norinyl and Ortho-Novum 1/50 or 1/80 rather than 1000% more progestational, and it makes Ovral 33% less progestational than Norinyl or Ortho-Novum 2 mg (Ortho Pharmaceutical Corp). This correlates closely with the relative progestational potency of these contraceptive pills as it is observed clinically. Androgenic activity ranges from 0% to 7.6% of the activity of orally administered methyltestoster-
OC sd u tion and management 549
one. Estrogenic activity ranges from 0% for norgestrel to 2.08 % of the activity of ethinyl estradiol adm inistered orally. Estrogenic act ivity of the progestogens is the result of metabolism to estrogenic compounds, usually 17,8-estradiol. The two estrogens utilized in the contraceptive pills, ethinyl estradiol and mestranol, are also metabolized into 17,8estradiol in vivo. The progestogens also exhibit ant iestrogenic activity in vivo. Antiestrogenic activity is greatest in those progestins with the hi ghest androgen ic activity. To understand how the antiestrogenic activity of progestins may play a clinically significant role in reducing certain estrogen act ions in the body, we must recall that the progestogens are not molecularly similar to progesterone but rather to testosterone and estrogen. Antiestrogenic activity is very likely the result of their metabolism to weakly active androgens and estrogens. Pharmacologic dose-response studies show that, when combined with estrogens, the progestogens act as partial agoniststhey potentiate activity at low doses and inhibit estrogenic activity at high doses (2). It is possible to express the comparative progestational and androgenic potency of contraceptive pills by multiplying the activity of the individual progestogens by the dose. In Table II, the order of ranking of pills is different for progestational and androgenic potencies, and some pills with low progestogen dosage are intermediate or high in progestational and androgenic potency. Progestational potency is probably the least important characteristic of contraceptive pills since there are few side effects associated with the progestogens and even the possible effect on hypertension may be due to the total steroid content of contraceptive pills and, therefore, would potentially be inversely proportional to the activity of individual progestogens. Androgenic action is important in the low-dose contraceptive pills where it is probably the principle means of contraception. Estrogen potency, as shown in Table II, was determined by two methods. The first and older method (A) assigns a potency to ethinyl estradiol 50 % greater than that of mestranol and considers only the dosage and potency of estrogen. The second, newer method (B) takes into account the effect of the progestogen on estrogen potency. Both methods use the uterine growth effect to determine estrogen potency (2). In A, only the growth effects of estrogen are considered. In B, the growth effects of the combined pill are considered. It has not yet been determined how closely estrogenic effects in the reproductive system are related to estrogen-induced effects in the cardiovascular
system, central nervous system and liver. There is, however, some clinical evidence that when the dosage of progestogen is increased relative to the dosage of estrogen, a reduction in the incidence of estrogeninduced thromboembolic disease may be noted (7, 8).
The capability of a pill to cause cyclic menstruation only during the pill-free days and to prevent spotting, staining or breakthrough bleeding during the days that active pills are being taken may be referred to as endometrial potency. Endometrial potency is the result of estrogenic, progestational and androgenic activity (Table II). It is closely related to delay of menses but should not be confused with it . In addition to the importance of the type and dosage of estrogen and progestin, the ratio between the two components is important. Because of differences in the way that bleeding is interpreted, it is best to combine breakthrough bleeding, staining and spotting and to refer to " total bleeding episodes." Generally, the incidence of bleeding decreases from the first cycle to the third cycle of pill use by 50%-66% per cycle. After the third cycle, it remains constant for the remainder of the first year. For this reason, comparing the incidence of total bleeding episodes in the third cycle of pill use is the most helpful method of comparing relative contraceptive pill potency. Table II shows the incidence of all forms of bleeding in the third cycle of pill use for Canada and the USA divided according to estrogen content. Attention is directed to the fact that the incidence of bleeding for some pills containing 30 J..Lg of estrogen is as low as that for some containing 50 J..L g of estrogen and that, even though pills containing 20 J..Lg of estrogen may have the highest incidence of bleeding of any combination pills, at least 69% of women might still be able to take them after the second cycle, without incident. Most pregnancies occurring in women who use contraceptive pills are due to patient failure- forgetting to take pills- rather than pill failure . There are no significant differences in the incidence of pill failure for the combination pills when these are tested under similar conditions. It might be expected that pregnancy rates would be higher with low-dose combination pills than with higher dose pills; however, the published figures do not support this expectation. The combined pregnancy rate due to both patient and pill failure for the 20-J..Lg pills is 0. 79I 100 woman-years (Pearl index), the rate for 30- 35-J..Lg estrogen pills is 0.131.36/100 woman-years and the rate for 50-J..Lg pills is 0.08- 0.88/100 woman-years (4).
lnl} Gynaecol Obslel 16
550
D ickey
Table II. Potency of oral contraceptives (A NA = not available)8 •
=
estrogen only, B
=
estrogen and progestogen); *
Estrogenic Potencyb Name
Therapeutic indication only Enovid 10 Enovid 5 NorinyiiOrtho-Novum 10 Ortho-Novum 5 Contraceptive-combination (more than 50 p.g of estrogen) Enovid E (21 )INovinol Ortho-Novum 0 .5 Ovulen (21) Ovulen 0 .5 NorinyiiOrtho-Novum 2 Norinyl I Ortho-Novum 1180 Contraceptive-combination. (50 p.g of estrogen) Anoryol Ovcon 50 Ovral LogestiNorlestriniZorane 1150 NorinyiiOrtho-Novum 1/50 Demulen Norlestrin 2 .5 Contraceptive-combination (less than 50 p.g of estrogen) Brevicon I Mod icon I M oda Con Ovcon 35 Lo-Ovral I M in-Ovral Loestrin I Logestl Zorane 1.5/30 MinEstriniLoestrin/ Zorane 1120 Contraceptive-progestogen only Nor Q.D./Micronor Ovrette 8
b
c d
e
=
estimated, Breakthrough Bleeding and Spotting 9
A
B
Progestational Potencyc
100 50 40 50
438 240 NA 76
0 .94 0.48 3.71 1.90
0.00 0 .00 3 .35 1.67
4.0 7.4 3.8 3.0
67 67 67 53 67 67
80 68 46 42 64 77
0 .25 0 .53 0 .74 0.38 0.26 0.19
0 .00 0.21 0.67 0.34 0.10 0.17
10.9 7.7 6.1 4.8 28.8 7.2
50 50 50 50
50 50* 42 39
0 .26 0.38 0.50 0.44
0.10 0 .34 0 .80 0.52
28.8 11.9 4.5 13.6
37
32
0 .38
0.34
10.6
50 50
26 16
0.53 1.02
0.21 1.25
13.4 5 .1
35
42
0.19
0.17
14.6
35 30 30
40* 25 14
0.15 0.30 0.65
0 .14 0.48 0.79
19.0 9.8 25.2
20
13
0.44
0 .52
30.9
0 0
6 0
0 .80 0 .10
0 .16 0 .16
42 .3 34.9
Androgenic Potencyd
Pills and manufacturers (in parentheses) include the following: Anoryol, Novinol (Desbergers Ltd, Montreal, Quebec, Canada); Logest 1.5/30 and 1/50, Zorane 1/20, 1/50 and 1.5/30 (Lederle Laboratories, Pearl River, NY, USA); Ovcon 35 and 50 (Mead Johnson Laboratories, Evansville, IN, USA); Micronor, Moda Con, Modicon, Ortho-Novum 0.5, 1/50, 11 80, 2, 5 and 10 (Ortho Pharmaceutical Corp, Raritan, NJ, USA); Loestrin 1.5/30 and 1/20, MinEstrin 1/20, Nor/estrin 2.5 and 1 I 50 (Parke, Davis & Co, Detroit, Ml, USA); Demulen, Enovid E (21) 5 and 10, Ovu/en (21) and 0. 5 (Searle Laboratories, Chicago, IL , USA); Brevicon, Norinyl 1/50, 1/80, 2 and 10, Nor Q.D. (Syntex Laboratories, Inc, Palo Alto, CA, USA); and Lo-Ovral, Min-Ovral, Ovral, Ovrette (Wyeth International, Philadelphia, PA, USA). Source: R. P. Dickey (4). Micrograms of ethinyl estradiol equivalents per day. Milligrams of norgestrel equivalents per day. Milligrams of methyl testosterone equivalents per 28 days. Information submitted to the FDA by the manufacturer on incidence in third cycle of pill use. These rates are derived from separate studies conducted by different investigators in several population groups and therefore a precise comparison cannot be made.
PATIENT CHARACTERISTICS Previous menstrual history
Nearly all pa tients may satisfactoril y take one of the pills conta ining 50 p.g or less of estrogen (Fig. 1) . l nt j Gynaecol Obstet / 6
The determining factors in selection of a pill are the type a nd amount of menses a nd menstrual discomfort usually experienced by a woman when not on her menstrual cycle. This is modified by other considera tions, such as weight and sensitivity to partie-
OC selection and management
55 I
Menatrual Chuacterlatlca
Type of PIU Indicated
Suggated Cbolc:ea t
Regular ~ght menses, 2-4 days' flow, mild or no cramps.
Low progestogen potency
Regular moderate menses, 4-6 days' flow, moderate cramps
Intermediate progestogen potency
Regular heavy menses, 6+ days' flow, severe or moderate cramps
High progestogen potency
Brevicon, Lo-Ovral, Moda Con, Modicon, Ovcon 35, Min-Ovral Demulen, Loestrin 1/20, Min-Ovral, Lo-Ovral, Norinyl 1/50, Norlestrin 1/50, Ovcon 50, Logest 1/50, Ovral, Ortho-Novum 1/50, Zorane 1/20 & 1/50, Anoryol, MinEstrin Loestrin 1.5/30, Norlestrin 2.5, Logest 1.5/30, Ovral, Zorane 1.5/30
Irregular & Infrequent menses, hypermenorrhea when occurs, associated acne, oily skin, hirsutism
Low androgen potency, 50 J.tg. estrogen pills; probable polycystic ovarian syndrome
Irregular menses, hypomenorrhea when occurs, no androgen effects
Oral contraceptives should not be used. Possible hypothalamic insufficiency. If galactorrhea present, skull x-ray or prolactin needed.
Patient Characteristics Age over ·35
Oral contraceptives are not recommended. If pills are used, select those with no estrogen or low estrogen.
Demulen, Norinyl 1/50, Ortho-Novum 1/50, Ovcon 50, Anoryol
Low Estrogen: Loestrin 1/20 & 1.5/30, Logest 1.5/30, Lo-Ovral, MinEstrin 1/20, Zorane 1/20 & 1.5/30, Min-Ovral No Estrogen: Micronor, Nor Q.D., Ovrette Brevicon, Lo-Ovral, Min-Ovral, Modicon, Ovcon 35, Moda Con
Weight under 110 lb.
Low estrogen & low progestogen
Weight over 160 lb.
High progestogen potency
History of toxemia, strong family history of hypertension, excessive weight gain, tiredness, or varicose veins during pregnancy, depression, excessive premenstrual edema
Low progestogen pills; monitor blood pressure
Excessive nausea, edema, or or hypertension in pregnancy. Hypertrophy of the cervix or uterus, uterine fibroids, large or fibrocystic breasts, heavy menses.
Low estrogen potency
Demulen, Loestrin 1/20 & 1.5/30, Lo-Ovral, Min-Ovral, Norlestrin 2.5, Zorane 1/20, Logest 1.5/30, Anoryol, MinEstrin
Surgery planned within 4 weeks
Progestogen-only pills or no pills
Micronor, Nor Q.D., Ovrette
Loestrin 1.5/30, Loges t 1.5/30, ~orlestrin 2.5, Ovral, Zorane 1. 5/30 Brevicon, Lo-Ovral, Min-Ovral, Modicon, Ovcon 35, Moda Con
Oral contraceptives should None not be used They can be started at the time of weaning. Fig. 1. Choice of initial oral contraceptive (pills containing 50 11-g or less of ethinyl estradiol or mestranol). tPills and manufacturers (in parentheses) include the following: Anoryol (Desbergers Ltd, Montreal, Quebec, Canada); Logest 1.5/30 and 1/50, Zorane 1/20, 1/50 and 1.5/30 (Lederle Laboratories, Pearl River, NY, USA); Ovcon 35 and 50 (Mead Johnson Laboratories, Evansville, IN, USA); Micronor, Moda Con, Modicon, Ortho-Novum 1/50 (Ortho Pharmaceutical Corp, Raritan, NJ, USA); Loestrin 1/20 and 1.5/30, MinEstrin, Norlestrin 2.5 and 1/50 (Parke, Davis & Co, Detroit, Ml, USA); Demulen (Searle Laboratories, Chicago, IL, USA); Brevicon, Norinyl 1/50, Nor Q.D. (Syntex Laboratories, Inc, Palo Alto, CA, USA); and Lo-Ovral, Min-Ovral, Ovral, Ovrette (Wyeth International, Philadelphia, PA, USA). Source: A. P. Dickey (4). Nursing
lntj Gy naecol Obslel 16
552
Dickey
ular types of side effects and particular risk factors which she may wish to avoid . Women who experience 2- 4 days of light flow and mild or no cramps will do well with the lowest doses of estrogen and progestogen. Those with average flow and average cramps do well with any pills of intermediate estrogenic and progestational strength. Women with normally heavy flow in either amount or duration and those who experience severe menstrual cramps require high progestational-androgenic potency. Before giving any of the strongly progestational-androgenic pills, the physician should determine that the patient has no unusual sensitivity to androgens. Women with infrequent or irregular menses are usually anovulatory and belong to one of two major types. The first type includes those with polycystic ovarian syndrome (Stein-Leventhal syndrome). They often have increased acne, secretion of sebum or hirsutism , a nd th eir menstru a l flow, when it occurs, is usua lly moderate-to-heavy a nd may be ovulatory. Although these patients require ovaria n suppression if th ey wish to have normal cycles, they may be unusually sensitive to androgen. It is preferable, therefore, to use only pills with low androgen potency. The second type of anovulatory women are those without androgen effects whose menses are often very scant and have less than normal breast development. These women may have a hypothala mic insufficiency and OCs should be avoided if possible, so long as further pregnancies are desired (4).
Initial weight Underweight women are more likely to experience side effects of hormone excess; however, they have less brea kthrough bleeding than normal weight and overweight women. They usually do best on pills with low estrogen and progestin potency. Overweight women experience less of the minor side effects usually associated with hormone excess during the first three cycles but, conversely, have more breakthrough bleeding, spotting or missed menses. It has been observed that overweight women also experience significantly less weight gain than normal or underweight women. Such women may be expected to do best on pills with higher progestogen, progesterone-androgen potency (9).
Hormone sensitivity Some women will have increased sensitivity to their own hormones. Such sensitivity becomes ap-
lnt j Gy naecol Obstet 16
parent during times of physiologic hormone excess, such as pregnancy, or even during the normal menstrual cycle. Women sensitive to progesterone often have excessive appetite, weight gain, tiredness and varicosities during pregnancy and may have excessive premenstrual edema and depression during their normal menstrual cycles. Women excessively sensitive to estrogen often have a past history of nausea, edema or even hypertension during pregnancy and during part of the menstrual cycle. Also included in this group are those women with enla rged uteri, uterine fibroids, cervical hypertrophy, large breasts, fibrocystic disease of the breast, heavy menses or marked cramps during menstruation . Other women may have symptoms indicating a lack of estrogen effect, such as scant menses, small uteri, small breasts, and mild midcycle or premenstrual spotting. These latter women should not be given higher doses of estrogen in order to stimulate a growth effect in these organs since their apparent lack of peripheral estrogen effects may be the result of their own internal regulation of estrogen production . Attempts to override this with excessive estrogen input may result in undesirable side effects (4, 5) . Women with excessive androgen effect , such as hirsutism, increased sebum and acne, do not always lack estrogen and, on the contrary, may also have hyperestrogenism as well. It is best to treat such women with pills with high progestational potency but low androgenic potency, such as those utilizing ethynodiol diacetate or norethynodrel as a progestogen. In selecting an initial OC, it is almost always best to begin with a low dosage of estrogen and to increase that dosage only if necessary. Since the most common side effect noted with low-estrogen pills is breakthrough bleeding or failure of withdrawal menses and since this may be treated equally well by increasing progestational-androgenic potency as by increasing estrogen dosage, consideration should always be given first to an increase or chan ge in the progestation component of the pill before an increase in estrogen dosage is made (4, 5). Women initially starting on the pill should be warned that their reproductive system will require 2-3 months to adjust to the usually lower doses of hormone furnished by pills and that they should wait at least this long for the side effects of bleeding to subside. On the other hand, they should be told that symptoms such as severe headache, numbness or tingling of the extremities on one side, visual changes or leg pain may precede a thromboembolic or cardiovascular accident and should be brought immediately to medical attention (Fig. 2) .
OC selection and management
Symptom
553
Possible Cause
I. Serious: Pills should be stopped immediately.
A Loss of vision, proptosis, diplopia, papilledema B. Unilateral numbness or weakness or tingling C. Severe chest pains, left arm or neck pain D. Hemoptysis E. Dyspnea F. Severe leg pains, tenderness or swelling, warmth or palpable cord G. Slurring of speech H. Hepatic mass or tenderness
A B. C. D. E.
Retinal artery thrombosis Hemorrhagic or thrombotic stroke Myocardial infarction Pulmonary embolism Myocardial infarction or pulmonary embolism F. Thrombophlebitis
G. Hemorrhagic or thrombotic stroke H. Liver neoplasm
II. Potentially serious: Pills may be continued with caution while the patient is being evaluated.
A B. C. D.
Absence of menses Spotting and breakthrough bleeding Breast mass, pain, or swelling Right upper quadrant pain
A B. C. D.
E. Mid epigastric pain
E.
F. Migraine (vascular or throbbing) headache G. Severe nonvascular headache H. Galactorrhea I. Jaundice, pruritus J. Depression K. Uterine size increase
F. G. H. I. J.
K.
Pregnancy (one cycle only) Cervical, endometrial, or vaginal cancer Breast cancer Cholecystitis, cholelithiasis, or liver neoplasm Thrombosis of abdominal artery or vein, myocardial infarct, or pulmonary embolism Vascular spasm preceding thrombosis Hypertension Pituitary adenoma Cholestatic jaundice B 12 deficiency Leiomyomata, adenomyosis, pregnancy
Fig. 2. Symptoms of a serious or potentially serious nature. Source: R. P. Dickey (3).
MANAGEMENT OF SIDE EFFECTS Although OCs produce effects in the body similar to those of natural sex hormones produced in the ovaries, they differ from ovarian steroids: I . In their pathway of entry into the bloodstream since they must enter the portal circulation first; 2. In their pattern of blood levels since they are administered as a single large dose once a day instead of a continuous secretion of low dose which is subject to day-to-day variation and is under the control of negative feedback from the pituitary; and 3. In their duration of action, which is prolonged by modificatiqn of their structures. Side effects occur when the hormone action of a pill is either too great or too little for a particular woman compared to the hormone action of her own ovarian steroids. Parallels to nearly all of the side effects of hormone excess from the pills can be found in the symptoms and physiologic changes of pregnancy. Parallels to the side effects of hormone deficiency can be found in the symptoms and changes
of the perimenopausal time of a woman's life. Most women taking pills which contain 50 f..l.g or less of estrogen will receive less hormone stimulation to the reproductive system and breasts than they formerly received from their ovarian steroids, but they will receive greater hormone stimulation to the liver and intestinal tract. Because of the similarity between the hormone effects in certain physiologic times of life and the side effects of the pills, these side effects may be grouped according to whether they are related to the estrogen or the progestogen component of the pill and further broken down depending on whether they are related to an excess or deficiency of a particular hormone (Fig. 3) . Estrogen side effects are not all of one type and can be subdivided into those related to the reproductive system, those related to the cardiovascular system and those of a general nature. Progestogen-excess symptoms can be subdivided into those du e to the progesta tiona l activity and those due to androgenic activity. Finally, there are a number of symptoms common to
lntj Gynaecol Obstet 16
554
Dickey
Estrogen Excess
Progestogen Excess Progestational Symptoms:
General & Vascular Symptoms:
Increase in serum proteins of hepatic origin (clottin!;! factors, renin substrate, thyroid binding globulin, steroid binding globulin)
Noncyclic weight gain Increased appetite Tiredness, fatigability
Elevated triglycerides, lower serum cholesterol
Depression
Telangiectasis, capillary fragility
Breast tenderness
Chloasma
Increase in breast size (alveolar tissue)
Urinary tract infections
Decreased libido
Hay fever & allergic rhinitis
Dilated leg veins Pelvic congestion syndrome
Chronic nasal pharyngitis Gastric influenza & varicella
Decreased days of flow
Vascular headaches (migraine)
Moniliasis
Hemiparesis (unilateral weakness & numbness)
Cervicitis
Thromboembolic disease
Neurodermatitis
Myocardial infarction
Hypertension (also Estrogen Excess)
Cerebrovascular disease (stroke)
Androgenic Symptoms:
Hypertension (also Progestogen Excess)
Oily skin & scalp
Reproductive System Symptoms:
Acne
Mucorrhea
Hirsuitism
Uterine enlargement
Rash & pruritus
Uterine fibroid growth
Cholestatic jaundice
Cervical exstrophy
Increased libido
Cystic breast changes Increase in breast size (ductal & fatty tissue) Hypermenorrhea, menorrhagia, dysmenorrhea (also progestogen deficiency)
Estrogen Excess U Occurs Owing Active Pill Days
~
Progestin Excess If Occurs During Plii-Free Days
Fluid Retention Symptoms: Nausea & vomiting Dizziness, syncope Edema, leg cramps Irritability Bloating Cyclic weight gain · Cyclic headaches Cyclic visual changes
Estrogen Deficiency
Progestogen Deficiency
Early spotting & bleeding, pill days 1 to 7 Continuous spotting & bleeding Decreased flow, hypomenorrhea No withdrawal menses Pelvic relaxation symptoms Nervousness Vasomotor symptoms Atrophic vaginitis, dyspareunia
. Late spotting & breadth rough bleeding, pill days 8 to 21 Heavy flow & clots (also estrogen excess) Dysmenorrhea (also estrogen excess) Delayed withdrawal bleeding Weight loss
Fig. 3. Relation of side effeGts to hormone content. Source: R. P. Dickey (4).
lntj Gynatcol Obstet 16
OC selection and management
the premenstrual part of the cycle which are related to fluid retention and which may be due to either excessive estrogen activity or excessive progestogen activity depending on where in the cycle they occur. Fig. 2 lists these symptoms according to their probable cause (4, 5) . The first step in the management of side effects is to decide what their probable etiology may be and whether they are due to excess estrogen or progestin or, perhaps, to deficiencies of estrogen or progestin. Care must be taken to determine when in the 28day cycle symptoms occur, since those which occur during the days when active pills are being taken may have different causes than the same symptoms occurring when inactive pills or no pills are being taken. The next step is to make a decision about the probable clinical course of the side effect if the pills are continued. Those side effects related to breakthrough bleeding generally improve between the first a nd third cycles of use. So, also, do side effect s such as nausea. On the other hand, the same side effects appearing after several cycles of pill use may not improve and may necessitate a change of pills. There are a few side effects which may be prodromal of a more serious complication (3). When these occur, the pills may need to be stopped immediately or continued only with caution (Fig. 2). When a decision is made to switch pills because of minor side effects, it can be done on the basis of either the drug dosage, in the case of estrogens, or progestogens in which more than one progestational dosage of the same progestin is available. However, when a switch to a different progestogen is contemplated, th e tables of potency contained in this discussion will provide a helpful guide to the probable outcome. Finally, time must be allowed for the patient to adjust to a new pill , just as when the pill is originally
555
started . When a change is made to a pill with less estrogen or progestational effect, it is usually necessary to make the change a t the beginning of a new pill cycle. But when a change is made to a pill with equal or greater estrogen or progestin effect, it can be made a t any time in the cycle.
REFERENCES I. Beral V, Kay CR : Morta lity a mong oral contracept ive users. La ncet 2:72 7, 1977 .
2. C hiha l HJW, Dickey RP, Pepl er R : Estrogen potency of oral contracepti ve pills. Am J Obstet Gynecol I 2 1:75 , 1975 . 3. Dickey RP : Di agnosis and management of pa tients with ora l contracep tive side effects. J Contin Educ Obstet Gynecol 20: 19, 1978. 4. Dickey RP: M a naging Contraceptive Pill Pa tients, 2nd ed . Creative Informa tics, Aspen, CO, USA, and London , Canada, 1977. 5. Dickey RP : The pill- physiology, pharmacology a nd clinical use. In Seminar on Family Pla nning (ed LB T yrer, AW lsenman, EG Knox), 2nd ed . American College of Obstetricians a nd Gynecologists, C hicago, 1974. 6. Dickey RP, Stone SC: Progestat ional potency of oral contraceptives. Obstet Gynecol 47:!06, 1976. 7. Inman WHW, Vessey MP, Westerholm Y, Engelund A: Thromboembolic disease and the steroida l cont ent of ora l contraceptives. Br Med J 2:203, 1970. 8. Royal College of General Practitioners: Oral Contraceptives and H ealth . Pitman M edical, London, 1974. 9. Talwar PP, Berger GS: Side effects of dru gs: the relation of body weight to side effects associated with oral contraceptives. Br Med J / : 1637, 1977.
Address for reprints: Ri chard P. Dickey Suite 640 5640 Read Ad New Orleans, LA 70127 USA
!ntj Gynaeco/ Obstet 16
J Gynaecol Obstet
16: 547- 555, 1979
Initial Pill Selection and Managing the Contraceptive Pill Patient Richard P. Dickey Department of Obstetrics and Gynecology, Louisiana State University College of Medicine, New Orleans, Louisiana, USA
ABSTRACT Dickey RP (Dept of Obstetrics and Gynecology, Louisiana State University College of Medicine, New Orleans, LA, USA). Initial pill selection and managing the contraceptive pill patient. lnt} Gynaecol Obstet 16: 547- 555, 1979 Contraceptive pill risk may be lowered and patient continuation rates increased by selecting a pill best suited to each patient's needs. Each contraceptive pill has a unique profile of activity which is dependent upon both the dosage and type of progestogen and estrogen. Patient characteristics, especially menstrual history, are helpful in choosing an initial pill (which should be low in estrogen), and patient and family histories are also valuable in helping determine whether use of the pill is contraindicated. Patients with a history of sensitivity to their own hormones are more likely to experience side effects on contraceptive pills, as also are underweight women. Knowledge of individual pill activities and potencies can be helpful in selecting the initial pill and in changing pills when nonserious side effects occur.
INTRODUCTION Although the risk associated with contraceptive pill use is less than the . risk associated with pregnancy at most ages, this risk might be further lowered by selecting a pill best suited to individual patient needs and avoiding pill use entirely in those patients with particularly bad personal or family histories (4). Since all of the serious side effects associated with contraceptive pill use-with the possible exception of hypertension, altered glucose metabolism and depression-are related to estrogen content, the most promising method of reducing risk seems to be the selection of pills with very low estrogen content. As the estrogen content of contraceptive pills is lowered, first the incidence of menstrual cycle irregularity, spotting or staining, breakthrough bleeding and absence of bleeding between periods is increased ; and ultimately, there is some loss of effectiveness.
The progestational component of the pill becomes correspondingly more important for menstrual cycle control and for contraceptive effect iveness as the estrogen content is lowered. Certain progestins are more effective than others in controlling menstrualrelated events and in contraceptive effectiveness (Table I). These two characteristics of progestogens are associated with their androgen potency. Contraceptive pills differ considerably in both their dosage and their potency (5). Patient characteristics, such as usual menstrual pattern, weight and history of symptoms during the menstrual cycle or pregnancy associated with estrogen, androgen or progesterone, may be correlated with the occurrence of menstrual cycle and other side effects of contraceptive pill use, and may, therefore, influence the choice of a contraceptive pill. Selection of an initial contraceptive pill is concerned with differences both in pills and in patients. There are certain conditions which are absolute contraindications to contraceptive pill use. These are: l. Thrombophlebitis, thromboembolic disorders, cerebrovascular disease, myocardial infarction or coronary artery disease, or a past history of these conditions; \. 2. Markedly impaired liver function; 3. Known or suspected carcinoma of the breast; 4. Known or suspected estrogen-dependent neoplasm; 5. Undiagnosed abnormal genital bleeding; and 6. Known or suspected pregnancy. In addition, there are conditions which predispose patients to the risk of cardiovascular disease. These are: type II hyperlipidemia, diabetes mellitus, hypertension, previous hypertension of pregnancy, obesity and smoking. All of these are associated with an increased risk of myocardial infarction in oral contraceptive (OC) users. This risk also increases with age after age 30, with duration of use and with the estrogen dosage ( l) . Varicose veins of the legs and obesity increase the risk of thrombophlebitis. Other conditions are relative contraindications lntj Gynaecol Obstet 16
548
Dickey
Table I. Progestogen potency". Progestational Compound
b
Estrogenic
Delay of Menses
Subnuclear Vacuolization
Ventral Prostate
Vaginal Epitheliumb
Antiestrogenic
1.000
1 .00
7.6
0.00
18.5
0.500
0.53
1.0
0.86
1.0
0.067 0.050 0.036
0.45 0.38 0.13
2.5 1.6 0.0
0.38 0.25 2.08
25.0 2.5 0.0
Norgestrel Ethynodiol diacetate Norethindrone acetate Norethindrone Norethynodrel 8
Androgenic
Source: R. P. Dickey (5). Ethinyl estradiol = 100%.
because they may worsen during pill use; however, in other cases, they may actually improve during pill use. These include fibrocystic disease of the breast, asthma, epilepsy, migraine headaches, depression, leiomyoma of the uterus, ulcerative colitis and other conditions known to be affected by pregnancy (8). Finally, certain family histories suggest an mcreased risk of cardiovascular disease. The presence of myocardial infarction, cerebrothrombosis or hemorrhage (stroke) and pulmonary embolism in close relatives (mother, father, brother or sister) before the age of 50 indicates a possible familial tendency. It is recommended that, when this history is present, OCs should either not be used or should be used with caution after considering the age of onset and possible predisposing factors in the relative (4).
PILL CHARACTERISTICS The number of pills available for contraceptive use in the countries represented at this meeting are: Australia, 31; Canada, 28; France, 15; Sweden, 19; United Kingdom, 18; and USA, 29. When those which are duplicates differing in name only are removed, there remain 15- 24 different OC pill formulations available in each country. In Canada, where there are 21 different formulations, 12 of these contain 50 p.g or less of estrogen. In the USA, where there are 20 different formulations, 13 contain 50 p.g or less of estrogen. Although there are little or no differences in effectiveness among these pills, there are major differences in the occurrence of menstrual-related events, spotting or staining, breakthrough bleeding and missed menses and in the estrogenic, progesta-
lntj Gynaecol Obstel /6
tiona! and androgenic potency of the different contraceptive pills. These differences are due to both the dosage and the specific characteristic activity of the different progestogens and estrogens in the pills. Table I shows the comparative progestational, androgenic and estrogenic activities of the five progestogens used in Canada and the USA. Progestational activity is expressed relative to the most potent drug, norgestrel, and is shown as determined by two different methods (6). The delay of menses test, used for many years, has an inherent flaw since estrogenic and androgenic actions of the progestins, which also influence menstrual activity, can only be partly compensated for by adding fixed amounts of estrogen to the progestogen being tested. Thus, norgestrel, the most potent progestogen in the delay of menses test, appears to be 20 times more progestational than norethindrone. This means that the pill Ovral (Wyeth Laboratories, Philadelphia, PA, USA) must be ten times more progestational than Norinyl l/50 and 1/80 (Syntex Laboratories, Inc, Palo Alto, CA, USA) or Ortho-Novum 1/50 and 1/ 80 (Ortho Pharmaceutical Corp, Raritan, NJ, USA). But this clearly is not the case. The other progestational test, induction of subnuclear vacuolization, is influenced very little or not at all by the estrogenic and androgenic action of progestogens. According to the subnuclear vacuolization test, norgestrel is 2.6 times as progestational as norethindrone. This makes Ovral 30% more progestational than Norinyl and Ortho-Novum 1/50 or 1/80 rather than 1000% more progestational, and it makes Ovral 33% less progestational than Norinyl or Ortho-Novum 2 mg (Ortho Pharmaceutical Corp). This correlates closely with the relative progestational potency of these contraceptive pills as it is observed clinically. Androgenic activity ranges from 0% to 7.6% of the activity of orally administered methyltestoster-
OC sd u tion and management 549
one. Estrogenic activity ranges from 0% for norgestrel to 2.08 % of the activity of ethinyl estradiol adm inistered orally. Estrogenic act ivity of the progestogens is the result of metabolism to estrogenic compounds, usually 17,8-estradiol. The two estrogens utilized in the contraceptive pills, ethinyl estradiol and mestranol, are also metabolized into 17,8estradiol in vivo. The progestogens also exhibit ant iestrogenic activity in vivo. Antiestrogenic activity is greatest in those progestins with the hi ghest androgen ic activity. To understand how the antiestrogenic activity of progestins may play a clinically significant role in reducing certain estrogen act ions in the body, we must recall that the progestogens are not molecularly similar to progesterone but rather to testosterone and estrogen. Antiestrogenic activity is very likely the result of their metabolism to weakly active androgens and estrogens. Pharmacologic dose-response studies show that, when combined with estrogens, the progestogens act as partial agoniststhey potentiate activity at low doses and inhibit estrogenic activity at high doses (2). It is possible to express the comparative progestational and androgenic potency of contraceptive pills by multiplying the activity of the individual progestogens by the dose. In Table II, the order of ranking of pills is different for progestational and androgenic potencies, and some pills with low progestogen dosage are intermediate or high in progestational and androgenic potency. Progestational potency is probably the least important characteristic of contraceptive pills since there are few side effects associated with the progestogens and even the possible effect on hypertension may be due to the total steroid content of contraceptive pills and, therefore, would potentially be inversely proportional to the activity of individual progestogens. Androgenic action is important in the low-dose contraceptive pills where it is probably the principle means of contraception. Estrogen potency, as shown in Table II, was determined by two methods. The first and older method (A) assigns a potency to ethinyl estradiol 50 % greater than that of mestranol and considers only the dosage and potency of estrogen. The second, newer method (B) takes into account the effect of the progestogen on estrogen potency. Both methods use the uterine growth effect to determine estrogen potency (2). In A, only the growth effects of estrogen are considered. In B, the growth effects of the combined pill are considered. It has not yet been determined how closely estrogenic effects in the reproductive system are related to estrogen-induced effects in the cardiovascular
system, central nervous system and liver. There is, however, some clinical evidence that when the dosage of progestogen is increased relative to the dosage of estrogen, a reduction in the incidence of estrogeninduced thromboembolic disease may be noted (7, 8).
The capability of a pill to cause cyclic menstruation only during the pill-free days and to prevent spotting, staining or breakthrough bleeding during the days that active pills are being taken may be referred to as endometrial potency. Endometrial potency is the result of estrogenic, progestational and androgenic activity (Table II). It is closely related to delay of menses but should not be confused with it . In addition to the importance of the type and dosage of estrogen and progestin, the ratio between the two components is important. Because of differences in the way that bleeding is interpreted, it is best to combine breakthrough bleeding, staining and spotting and to refer to " total bleeding episodes." Generally, the incidence of bleeding decreases from the first cycle to the third cycle of pill use by 50%-66% per cycle. After the third cycle, it remains constant for the remainder of the first year. For this reason, comparing the incidence of total bleeding episodes in the third cycle of pill use is the most helpful method of comparing relative contraceptive pill potency. Table II shows the incidence of all forms of bleeding in the third cycle of pill use for Canada and the USA divided according to estrogen content. Attention is directed to the fact that the incidence of bleeding for some pills containing 30 J..Lg of estrogen is as low as that for some containing 50 J..L g of estrogen and that, even though pills containing 20 J..Lg of estrogen may have the highest incidence of bleeding of any combination pills, at least 69% of women might still be able to take them after the second cycle, without incident. Most pregnancies occurring in women who use contraceptive pills are due to patient failure- forgetting to take pills- rather than pill failure . There are no significant differences in the incidence of pill failure for the combination pills when these are tested under similar conditions. It might be expected that pregnancy rates would be higher with low-dose combination pills than with higher dose pills; however, the published figures do not support this expectation. The combined pregnancy rate due to both patient and pill failure for the 20-J..Lg pills is 0. 79I 100 woman-years (Pearl index), the rate for 30- 35-J..Lg estrogen pills is 0.131.36/100 woman-years and the rate for 50-J..Lg pills is 0.08- 0.88/100 woman-years (4).
lnl} Gynaecol Obslel 16
550
D ickey
Table II. Potency of oral contraceptives (A NA = not available)8 •
=
estrogen only, B
=
estrogen and progestogen); *
Estrogenic Potencyb Name
Therapeutic indication only Enovid 10 Enovid 5 NorinyiiOrtho-Novum 10 Ortho-Novum 5 Contraceptive-combination (more than 50 p.g of estrogen) Enovid E (21 )INovinol Ortho-Novum 0 .5 Ovulen (21) Ovulen 0 .5 NorinyiiOrtho-Novum 2 Norinyl I Ortho-Novum 1180 Contraceptive-combination. (50 p.g of estrogen) Anoryol Ovcon 50 Ovral LogestiNorlestriniZorane 1150 NorinyiiOrtho-Novum 1/50 Demulen Norlestrin 2 .5 Contraceptive-combination (less than 50 p.g of estrogen) Brevicon I Mod icon I M oda Con Ovcon 35 Lo-Ovral I M in-Ovral Loestrin I Logestl Zorane 1.5/30 MinEstriniLoestrin/ Zorane 1120 Contraceptive-progestogen only Nor Q.D./Micronor Ovrette 8
b
c d
e
=
estimated, Breakthrough Bleeding and Spotting 9
A
B
Progestational Potencyc
100 50 40 50
438 240 NA 76
0 .94 0.48 3.71 1.90
0.00 0 .00 3 .35 1.67
4.0 7.4 3.8 3.0
67 67 67 53 67 67
80 68 46 42 64 77
0 .25 0 .53 0 .74 0.38 0.26 0.19
0 .00 0.21 0.67 0.34 0.10 0.17
10.9 7.7 6.1 4.8 28.8 7.2
50 50 50 50
50 50* 42 39
0 .26 0.38 0.50 0.44
0.10 0 .34 0 .80 0.52
28.8 11.9 4.5 13.6
37
32
0 .38
0.34
10.6
50 50
26 16
0.53 1.02
0.21 1.25
13.4 5 .1
35
42
0.19
0.17
14.6
35 30 30
40* 25 14
0.15 0.30 0.65
0 .14 0.48 0.79
19.0 9.8 25.2
20
13
0.44
0 .52
30.9
0 0
6 0
0 .80 0 .10
0 .16 0 .16
42 .3 34.9
Androgenic Potencyd
Pills and manufacturers (in parentheses) include the following: Anoryol, Novinol (Desbergers Ltd, Montreal, Quebec, Canada); Logest 1.5/30 and 1/50, Zorane 1/20, 1/50 and 1.5/30 (Lederle Laboratories, Pearl River, NY, USA); Ovcon 35 and 50 (Mead Johnson Laboratories, Evansville, IN, USA); Micronor, Moda Con, Modicon, Ortho-Novum 0.5, 1/50, 11 80, 2, 5 and 10 (Ortho Pharmaceutical Corp, Raritan, NJ, USA); Loestrin 1.5/30 and 1/20, MinEstrin 1/20, Nor/estrin 2.5 and 1 I 50 (Parke, Davis & Co, Detroit, Ml, USA); Demulen, Enovid E (21) 5 and 10, Ovu/en (21) and 0. 5 (Searle Laboratories, Chicago, IL , USA); Brevicon, Norinyl 1/50, 1/80, 2 and 10, Nor Q.D. (Syntex Laboratories, Inc, Palo Alto, CA, USA); and Lo-Ovral, Min-Ovral, Ovral, Ovrette (Wyeth International, Philadelphia, PA, USA). Source: R. P. Dickey (4). Micrograms of ethinyl estradiol equivalents per day. Milligrams of norgestrel equivalents per day. Milligrams of methyl testosterone equivalents per 28 days. Information submitted to the FDA by the manufacturer on incidence in third cycle of pill use. These rates are derived from separate studies conducted by different investigators in several population groups and therefore a precise comparison cannot be made.
PATIENT CHARACTERISTICS Previous menstrual history
Nearly all pa tients may satisfactoril y take one of the pills conta ining 50 p.g or less of estrogen (Fig. 1) . l nt j Gynaecol Obstet / 6
The determining factors in selection of a pill are the type a nd amount of menses a nd menstrual discomfort usually experienced by a woman when not on her menstrual cycle. This is modified by other considera tions, such as weight and sensitivity to partie-
OC selection and management
55 I
Menatrual Chuacterlatlca
Type of PIU Indicated
Suggated Cbolc:ea t
Regular ~ght menses, 2-4 days' flow, mild or no cramps.
Low progestogen potency
Regular moderate menses, 4-6 days' flow, moderate cramps
Intermediate progestogen potency
Regular heavy menses, 6+ days' flow, severe or moderate cramps
High progestogen potency
Brevicon, Lo-Ovral, Moda Con, Modicon, Ovcon 35, Min-Ovral Demulen, Loestrin 1/20, Min-Ovral, Lo-Ovral, Norinyl 1/50, Norlestrin 1/50, Ovcon 50, Logest 1/50, Ovral, Ortho-Novum 1/50, Zorane 1/20 & 1/50, Anoryol, MinEstrin Loestrin 1.5/30, Norlestrin 2.5, Logest 1.5/30, Ovral, Zorane 1.5/30
Irregular & Infrequent menses, hypermenorrhea when occurs, associated acne, oily skin, hirsutism
Low androgen potency, 50 J.tg. estrogen pills; probable polycystic ovarian syndrome
Irregular menses, hypomenorrhea when occurs, no androgen effects
Oral contraceptives should not be used. Possible hypothalamic insufficiency. If galactorrhea present, skull x-ray or prolactin needed.
Patient Characteristics Age over ·35
Oral contraceptives are not recommended. If pills are used, select those with no estrogen or low estrogen.
Demulen, Norinyl 1/50, Ortho-Novum 1/50, Ovcon 50, Anoryol
Low Estrogen: Loestrin 1/20 & 1.5/30, Logest 1.5/30, Lo-Ovral, MinEstrin 1/20, Zorane 1/20 & 1.5/30, Min-Ovral No Estrogen: Micronor, Nor Q.D., Ovrette Brevicon, Lo-Ovral, Min-Ovral, Modicon, Ovcon 35, Moda Con
Weight under 110 lb.
Low estrogen & low progestogen
Weight over 160 lb.
High progestogen potency
History of toxemia, strong family history of hypertension, excessive weight gain, tiredness, or varicose veins during pregnancy, depression, excessive premenstrual edema
Low progestogen pills; monitor blood pressure
Excessive nausea, edema, or or hypertension in pregnancy. Hypertrophy of the cervix or uterus, uterine fibroids, large or fibrocystic breasts, heavy menses.
Low estrogen potency
Demulen, Loestrin 1/20 & 1.5/30, Lo-Ovral, Min-Ovral, Norlestrin 2.5, Zorane 1/20, Logest 1.5/30, Anoryol, MinEstrin
Surgery planned within 4 weeks
Progestogen-only pills or no pills
Micronor, Nor Q.D., Ovrette
Loestrin 1.5/30, Loges t 1.5/30, ~orlestrin 2.5, Ovral, Zorane 1. 5/30 Brevicon, Lo-Ovral, Min-Ovral, Modicon, Ovcon 35, Moda Con
Oral contraceptives should None not be used They can be started at the time of weaning. Fig. 1. Choice of initial oral contraceptive (pills containing 50 11-g or less of ethinyl estradiol or mestranol). tPills and manufacturers (in parentheses) include the following: Anoryol (Desbergers Ltd, Montreal, Quebec, Canada); Logest 1.5/30 and 1/50, Zorane 1/20, 1/50 and 1.5/30 (Lederle Laboratories, Pearl River, NY, USA); Ovcon 35 and 50 (Mead Johnson Laboratories, Evansville, IN, USA); Micronor, Moda Con, Modicon, Ortho-Novum 1/50 (Ortho Pharmaceutical Corp, Raritan, NJ, USA); Loestrin 1/20 and 1.5/30, MinEstrin, Norlestrin 2.5 and 1/50 (Parke, Davis & Co, Detroit, Ml, USA); Demulen (Searle Laboratories, Chicago, IL, USA); Brevicon, Norinyl 1/50, Nor Q.D. (Syntex Laboratories, Inc, Palo Alto, CA, USA); and Lo-Ovral, Min-Ovral, Ovral, Ovrette (Wyeth International, Philadelphia, PA, USA). Source: A. P. Dickey (4). Nursing
lntj Gy naecol Obslel 16
552
Dickey
ular types of side effects and particular risk factors which she may wish to avoid . Women who experience 2- 4 days of light flow and mild or no cramps will do well with the lowest doses of estrogen and progestogen. Those with average flow and average cramps do well with any pills of intermediate estrogenic and progestational strength. Women with normally heavy flow in either amount or duration and those who experience severe menstrual cramps require high progestational-androgenic potency. Before giving any of the strongly progestational-androgenic pills, the physician should determine that the patient has no unusual sensitivity to androgens. Women with infrequent or irregular menses are usually anovulatory and belong to one of two major types. The first type includes those with polycystic ovarian syndrome (Stein-Leventhal syndrome). They often have increased acne, secretion of sebum or hirsutism , a nd th eir menstru a l flow, when it occurs, is usua lly moderate-to-heavy a nd may be ovulatory. Although these patients require ovaria n suppression if th ey wish to have normal cycles, they may be unusually sensitive to androgen. It is preferable, therefore, to use only pills with low androgen potency. The second type of anovulatory women are those without androgen effects whose menses are often very scant and have less than normal breast development. These women may have a hypothala mic insufficiency and OCs should be avoided if possible, so long as further pregnancies are desired (4).
Initial weight Underweight women are more likely to experience side effects of hormone excess; however, they have less brea kthrough bleeding than normal weight and overweight women. They usually do best on pills with low estrogen and progestin potency. Overweight women experience less of the minor side effects usually associated with hormone excess during the first three cycles but, conversely, have more breakthrough bleeding, spotting or missed menses. It has been observed that overweight women also experience significantly less weight gain than normal or underweight women. Such women may be expected to do best on pills with higher progestogen, progesterone-androgen potency (9).
Hormone sensitivity Some women will have increased sensitivity to their own hormones. Such sensitivity becomes ap-
lnt j Gy naecol Obstet 16
parent during times of physiologic hormone excess, such as pregnancy, or even during the normal menstrual cycle. Women sensitive to progesterone often have excessive appetite, weight gain, tiredness and varicosities during pregnancy and may have excessive premenstrual edema and depression during their normal menstrual cycles. Women excessively sensitive to estrogen often have a past history of nausea, edema or even hypertension during pregnancy and during part of the menstrual cycle. Also included in this group are those women with enla rged uteri, uterine fibroids, cervical hypertrophy, large breasts, fibrocystic disease of the breast, heavy menses or marked cramps during menstruation . Other women may have symptoms indicating a lack of estrogen effect, such as scant menses, small uteri, small breasts, and mild midcycle or premenstrual spotting. These latter women should not be given higher doses of estrogen in order to stimulate a growth effect in these organs since their apparent lack of peripheral estrogen effects may be the result of their own internal regulation of estrogen production . Attempts to override this with excessive estrogen input may result in undesirable side effects (4, 5) . Women with excessive androgen effect , such as hirsutism, increased sebum and acne, do not always lack estrogen and, on the contrary, may also have hyperestrogenism as well. It is best to treat such women with pills with high progestational potency but low androgenic potency, such as those utilizing ethynodiol diacetate or norethynodrel as a progestogen. In selecting an initial OC, it is almost always best to begin with a low dosage of estrogen and to increase that dosage only if necessary. Since the most common side effect noted with low-estrogen pills is breakthrough bleeding or failure of withdrawal menses and since this may be treated equally well by increasing progestational-androgenic potency as by increasing estrogen dosage, consideration should always be given first to an increase or chan ge in the progestation component of the pill before an increase in estrogen dosage is made (4, 5). Women initially starting on the pill should be warned that their reproductive system will require 2-3 months to adjust to the usually lower doses of hormone furnished by pills and that they should wait at least this long for the side effects of bleeding to subside. On the other hand, they should be told that symptoms such as severe headache, numbness or tingling of the extremities on one side, visual changes or leg pain may precede a thromboembolic or cardiovascular accident and should be brought immediately to medical attention (Fig. 2) .
OC selection and management
Symptom
553
Possible Cause
I. Serious: Pills should be stopped immediately.
A Loss of vision, proptosis, diplopia, papilledema B. Unilateral numbness or weakness or tingling C. Severe chest pains, left arm or neck pain D. Hemoptysis E. Dyspnea F. Severe leg pains, tenderness or swelling, warmth or palpable cord G. Slurring of speech H. Hepatic mass or tenderness
A B. C. D. E.
Retinal artery thrombosis Hemorrhagic or thrombotic stroke Myocardial infarction Pulmonary embolism Myocardial infarction or pulmonary embolism F. Thrombophlebitis
G. Hemorrhagic or thrombotic stroke H. Liver neoplasm
II. Potentially serious: Pills may be continued with caution while the patient is being evaluated.
A B. C. D.
Absence of menses Spotting and breakthrough bleeding Breast mass, pain, or swelling Right upper quadrant pain
A B. C. D.
E. Mid epigastric pain
E.
F. Migraine (vascular or throbbing) headache G. Severe nonvascular headache H. Galactorrhea I. Jaundice, pruritus J. Depression K. Uterine size increase
F. G. H. I. J.
K.
Pregnancy (one cycle only) Cervical, endometrial, or vaginal cancer Breast cancer Cholecystitis, cholelithiasis, or liver neoplasm Thrombosis of abdominal artery or vein, myocardial infarct, or pulmonary embolism Vascular spasm preceding thrombosis Hypertension Pituitary adenoma Cholestatic jaundice B 12 deficiency Leiomyomata, adenomyosis, pregnancy
Fig. 2. Symptoms of a serious or potentially serious nature. Source: R. P. Dickey (3).
MANAGEMENT OF SIDE EFFECTS Although OCs produce effects in the body similar to those of natural sex hormones produced in the ovaries, they differ from ovarian steroids: I . In their pathway of entry into the bloodstream since they must enter the portal circulation first; 2. In their pattern of blood levels since they are administered as a single large dose once a day instead of a continuous secretion of low dose which is subject to day-to-day variation and is under the control of negative feedback from the pituitary; and 3. In their duration of action, which is prolonged by modificatiqn of their structures. Side effects occur when the hormone action of a pill is either too great or too little for a particular woman compared to the hormone action of her own ovarian steroids. Parallels to nearly all of the side effects of hormone excess from the pills can be found in the symptoms and physiologic changes of pregnancy. Parallels to the side effects of hormone deficiency can be found in the symptoms and changes
of the perimenopausal time of a woman's life. Most women taking pills which contain 50 f..l.g or less of estrogen will receive less hormone stimulation to the reproductive system and breasts than they formerly received from their ovarian steroids, but they will receive greater hormone stimulation to the liver and intestinal tract. Because of the similarity between the hormone effects in certain physiologic times of life and the side effects of the pills, these side effects may be grouped according to whether they are related to the estrogen or the progestogen component of the pill and further broken down depending on whether they are related to an excess or deficiency of a particular hormone (Fig. 3) . Estrogen side effects are not all of one type and can be subdivided into those related to the reproductive system, those related to the cardiovascular system and those of a general nature. Progestogen-excess symptoms can be subdivided into those du e to the progesta tiona l activity and those due to androgenic activity. Finally, there are a number of symptoms common to
lntj Gynaecol Obstet 16
554
Dickey
Estrogen Excess
Progestogen Excess Progestational Symptoms:
General & Vascular Symptoms:
Increase in serum proteins of hepatic origin (clottin!;! factors, renin substrate, thyroid binding globulin, steroid binding globulin)
Noncyclic weight gain Increased appetite Tiredness, fatigability
Elevated triglycerides, lower serum cholesterol
Depression
Telangiectasis, capillary fragility
Breast tenderness
Chloasma
Increase in breast size (alveolar tissue)
Urinary tract infections
Decreased libido
Hay fever & allergic rhinitis
Dilated leg veins Pelvic congestion syndrome
Chronic nasal pharyngitis Gastric influenza & varicella
Decreased days of flow
Vascular headaches (migraine)
Moniliasis
Hemiparesis (unilateral weakness & numbness)
Cervicitis
Thromboembolic disease
Neurodermatitis
Myocardial infarction
Hypertension (also Estrogen Excess)
Cerebrovascular disease (stroke)
Androgenic Symptoms:
Hypertension (also Progestogen Excess)
Oily skin & scalp
Reproductive System Symptoms:
Acne
Mucorrhea
Hirsuitism
Uterine enlargement
Rash & pruritus
Uterine fibroid growth
Cholestatic jaundice
Cervical exstrophy
Increased libido
Cystic breast changes Increase in breast size (ductal & fatty tissue) Hypermenorrhea, menorrhagia, dysmenorrhea (also progestogen deficiency)
Estrogen Excess U Occurs Owing Active Pill Days
~
Progestin Excess If Occurs During Plii-Free Days
Fluid Retention Symptoms: Nausea & vomiting Dizziness, syncope Edema, leg cramps Irritability Bloating Cyclic weight gain · Cyclic headaches Cyclic visual changes
Estrogen Deficiency
Progestogen Deficiency
Early spotting & bleeding, pill days 1 to 7 Continuous spotting & bleeding Decreased flow, hypomenorrhea No withdrawal menses Pelvic relaxation symptoms Nervousness Vasomotor symptoms Atrophic vaginitis, dyspareunia
. Late spotting & breadth rough bleeding, pill days 8 to 21 Heavy flow & clots (also estrogen excess) Dysmenorrhea (also estrogen excess) Delayed withdrawal bleeding Weight loss
Fig. 3. Relation of side effeGts to hormone content. Source: R. P. Dickey (4).
lntj Gynatcol Obstet 16
OC selection and management
the premenstrual part of the cycle which are related to fluid retention and which may be due to either excessive estrogen activity or excessive progestogen activity depending on where in the cycle they occur. Fig. 2 lists these symptoms according to their probable cause (4, 5) . The first step in the management of side effects is to decide what their probable etiology may be and whether they are due to excess estrogen or progestin or, perhaps, to deficiencies of estrogen or progestin. Care must be taken to determine when in the 28day cycle symptoms occur, since those which occur during the days when active pills are being taken may have different causes than the same symptoms occurring when inactive pills or no pills are being taken. The next step is to make a decision about the probable clinical course of the side effect if the pills are continued. Those side effects related to breakthrough bleeding generally improve between the first a nd third cycles of use. So, also, do side effect s such as nausea. On the other hand, the same side effects appearing after several cycles of pill use may not improve and may necessitate a change of pills. There are a few side effects which may be prodromal of a more serious complication (3). When these occur, the pills may need to be stopped immediately or continued only with caution (Fig. 2). When a decision is made to switch pills because of minor side effects, it can be done on the basis of either the drug dosage, in the case of estrogens, or progestogens in which more than one progestational dosage of the same progestin is available. However, when a switch to a different progestogen is contemplated, th e tables of potency contained in this discussion will provide a helpful guide to the probable outcome. Finally, time must be allowed for the patient to adjust to a new pill , just as when the pill is originally
555
started . When a change is made to a pill with less estrogen or progestational effect, it is usually necessary to make the change a t the beginning of a new pill cycle. But when a change is made to a pill with equal or greater estrogen or progestin effect, it can be made a t any time in the cycle.
REFERENCES I. Beral V, Kay CR : Morta lity a mong oral contracept ive users. La ncet 2:72 7, 1977 .
2. C hiha l HJW, Dickey RP, Pepl er R : Estrogen potency of oral contracepti ve pills. Am J Obstet Gynecol I 2 1:75 , 1975 . 3. Dickey RP : Di agnosis and management of pa tients with ora l contracep tive side effects. J Contin Educ Obstet Gynecol 20: 19, 1978. 4. Dickey RP: M a naging Contraceptive Pill Pa tients, 2nd ed . Creative Informa tics, Aspen, CO, USA, and London , Canada, 1977. 5. Dickey RP : The pill- physiology, pharmacology a nd clinical use. In Seminar on Family Pla nning (ed LB T yrer, AW lsenman, EG Knox), 2nd ed . American College of Obstetricians a nd Gynecologists, C hicago, 1974. 6. Dickey RP, Stone SC: Progestat ional potency of oral contraceptives. Obstet Gynecol 47:!06, 1976. 7. Inman WHW, Vessey MP, Westerholm Y, Engelund A: Thromboembolic disease and the steroida l cont ent of ora l contraceptives. Br Med J 2:203, 1970. 8. Royal College of General Practitioners: Oral Contraceptives and H ealth . Pitman M edical, London, 1974. 9. Talwar PP, Berger GS: Side effects of dru gs: the relation of body weight to side effects associated with oral contraceptives. Br Med J / : 1637, 1977.
Address for reprints: Ri chard P. Dickey Suite 640 5640 Read Ad New Orleans, LA 70127 USA
!ntj Gynaeco/ Obstet 16
