J. chron. Dis. 1965, Vol. 18, pp. 1141-1146. Pergamon Press Ltd. Printed in Great Britain

CLINICAL USE OF ORAL CONTRACEPTION*

EDWARD T. TYLER

AT PRESENT, clinical use of oral contraceptives involves the woman's taking one pill a day for 20 days, starting on the 5th day of the menstrual cycle (the 1st day being considered the 1st day of menstruation). After the 20-day course of pills is taken, bleeding will usually occur within 2-3 days and another course of pills is begun again on the 5th day, and so on. There may be some modification in the dosage schedule by the time this appears in print, particularly to a 21-day course.

After 9 years of clinical study, it is safe to say that oral contraception with progestational agents such as norethynodrel, norethindrone and similar compounds (combined with an estrogen) is extremely effective. Some believe that this form of contraception is 100 per cent effective when used properly. Many studies would support this conclusion but it is dangerous to ascribe total effectiveness to anything in medicine, and for this reason `close to 100 per cent effective' would be more accurate. During these years it has been found that there are certain medical problems associated with the use of the oral contraceptives. Some problems are very minor, whereas others are potentially serious. In the former class are the relatively minor problems of gastrointestinal disturbances, breakthrough bleeding, headaches, breast soreness, weight changes, and a variety of other complaints which, in the majority of cases, are not significant enough to warrant discontinuing the use of the contraceptive. In the class of serious problems is the present unanswered question of a possible relationship between oral contraception and abnormal blood clotting, which will be discussed in some detail later in this report.

From the beginning of the use of these agents, some of the most annoying side effects have been the occurrence of nausea, occasional vomiting, and other gastrointestinal disturbances. The incidence of these problems seems to vary somewhat with different preparations and dosage combinations (and there are now several preparations currently marketed in the United States, and many additional ones in various other countries), as well as with the population group involved and with the investigator. It is undoubtedly fair to say in summary at this time, that in the vast majority of patients these particular side-effects will subside if the patient continues to take the medication. She will acquire a tolerance and ultimately will not be bothered by the complaints. It is generally agreed that the gastrointestinal disturbances are primarily attributable to the estrogenic hormone content of the pills.

Another well-recognized finding in studies of oral contraception is that a fair percentage of patients will have `breakthrough bleeding' (bleeding at times other than during the menstrual period) at some time during the administration of these pills, often for several days in a given cycle or perhaps just for a single day with only slight spotting. The exact reason for breakthrough bleeding is somewhat obscure but

it may well be related to irregularity in absorption of the hormone so that there is, in effect, a temporary withdrawal of hormone for a given time which permits the uterine lining to start to desquamate. This is most likely to occur when a few pills are omitted. While breakthrough bleeding is a nuisance, it is generally agreed that it is not a serious enough problem to warrant limiting the use of this type of oral contraception. With proper instruction and education, if these can be made available, women can be reassured adequately enough to continue using the pills. In a similar category is the problem of amenorrhea. Some patients may not bleed after they have taken the last tablet in a cycle and this, of course, produces the added concern of a possible pregnancy. In our own studies, some women have used as many as seven cycles of pills with no bleeding between cycles. This also has been the experience of several other investigators. In many clinics, patients are now given instructions to resume medication 7-8 days following the last pill whether bleeding has occurred or not.

One of the serious recent questions, as mentioned previously, relates to whether this type of oral contraception can produce spontaneous clotting in blood Nessels. Several cases of thrombophlebitis among oral contraceptive users have been reported, as well as the more serious incidents of pulmonary embolism or cerebral embolism. It has been extremely important to determine whether there is a relationship between the medication and the occurrence of embolism. Unfortunately, it is almost an impossible task to determine whether there is a relationship. The mechanism of blood coagulation is so complicated that even elaborate series of tests cannot definitely indicate whether abnormal results, even if found, suggest increased or decreased tendency for the blood to clot spontaneously.' After obtaining results that were interpreted differently by six hematologists we discarded this type of study. Since it is well known that thrombophlebitis and pulmonary embolism can occur spontaneously it has become important to know the incidence of spontaneously occurring clotting problems among oral contraceptive users compared with the general female population in the same age groups. These statistics are extremely difficult to obtain, but efforts are currently being made in this direction. The data in Table 1, from the National Disease and Therapeutic index refer to this problem. According to figures available, some statisticians claim that the total number of cases of thrombotic

disorders thus far among pill users is actually about 50 per cent of what might have been expected, considering the total number of women now using oral contraception.
The possibility of a relationship between the use of synthetic progestational compounds as oral contraceptives and the occurrence of intravascular clotting was first suspected late in 1961, when fatal pulmonary embolism occurred in two young Los Angeles women who had been using oral contraceptives. Since then several additional cases have been recorded. From 1961 to the present time, 347 instances of thrombophlebitis (or phlebothrombosis) among women using a norethynodrel-estrogen combination, norethynodrel with mestranol (Enovid), for contraception have been reported to the manufacturer. In the same period, fatal pulmonary embolism has occurred in 35 cases, but in many there were other likely etiological factors, and at least 9 were due to other causes.

When the initial cases of pulmonary embolism came to light, the United States Food and Drug Administration (FDA) investigators looked into the specific cases but were unable to conclude that there was a definite cause-and-effect relationship. Undoubtedly because of the suspicion cast and, presumably, the nonvital nature of oral contraception as a drug indication, the FDA required the manufacturer to send a warning letter to all physicians, suggesting that norethynodrel with mestranol should not be used for oral contraception in women with a tendency toward thrombophlebitis. (It should be noted, though, that while most cases of thrombophlebitis occurred in women with a related past history, many were found among women who gave no history of previous vascular disorders.)

Therefore, there is still no definite evidence linking thrombophlebitis with oral contraception, but at the time of this writing the matter is not completely resolved.3 There is undoubtedly still a question of rare individual patient idiosyncrasy to the drugs involved, with resultant increased coagulation tendencies.

RESULTS OF CLINICAL STUDIES IN LOS ANGELES

Since the initial use of progestagen-estrogen contraception, a substantial number of combinations of such agents have been studied and are under study at our clinic. The first preparation to be used on a large scale was the combination of norethynodrel, 10 mg, with 0.15 mg of 3-methylether or ethinyl-estradiol (mestranol). This combination was first studied by Pincus and his collaborators in Puerto Rico beginning in 1956. Shortly afterwards we began a study of a combination of norethindrone, 10 mg, with mestranol, 0.06 mg, and a little later we also began studying the same 10 mg norethynodrel tablet that was being used in Puerto Rico. After the 10 mg norethynodrel tablet had been in use a few years an attempt was made to find a practical lower dosage preparation. Therefore, a tablet was evaluated which contained 5 mg norethynodrel with 0.075 mg mestranol. This particular combination seemed equally effective as the 10 mg preparation, and there were fewer side-effects, notably those that related to the gastrointestinal tract. Once the 5 mg dosage had been approved, further attempts were initiated to reduce the dosage. This resulted in the development of tablets containing 2.5 mg norethynodrel with 0.1 mg mestranol and also tablets containing 2 mg norethindrone with 0.1 mg mestranol. At the time of preparation of this report both the 2 mg norethindrone and the 2.5 mg norethynodrel tablets are on the market in the United States, as well as a 2.5 mg norethindrone acetate combination. Also now available are: a 10 mg medroxy-progesteroneethmyl estradial preparation, and two `sequential' preparations (as discussed below). In the testing stage are combinations containing as little as 1 mg. and 0.5 mg of the progestagens, and results with these are encouraging. We have tabulated our experiences with norethynodrel and a new progestagen in 1 mg doses and the summaries are given in Tables 2, 3, and 4, to early in 1964.

In various journals from time to time we have reported our experiences with these preparations. Others have reported extensive experiences with similar compounds. The reader is referred to the reports of Pincus, Rock, Garcia, Rice-Wray, Satterthwaite, Goldzieher, Mears and others. A selection of these reports is listed below.

Sequential therapy

Following the demonstration of satisfactory results with the type of progestagenestrogen contraception described above, and while recognizing that these preparations can be utilized in relatively low dosages, additional measures have been taken in the direction of lowering the overall hormone content of the contraceptive pills. A major step in this direction was the development of so-called `sequential' contraception. With this method estrogen alone is used for the first part and then the combination of progestagen and estrogen is used for the last part of treatment. The usefulness

of this method is based on the well-known fact that estrogens alone can inhibit ovulation. Hence, when adequate amounts of estrogen are given during the first portion of the cycle, ovulation can be prevented and the combination of progestagen and estrogen late in the cycle allows for adequate development of the endometrium so that the usual withdrawal bleeding is obtained. This form of contraception has now been in use for about four years and seems to be working quite well. It has certain advantages, namely, that the total amount of hormone administered is less than that with the usual dosage of the combined tablet. Secondly, the progestagen is the more expensive component of the oral contraceptive tablets and, with this method; the combined tablet is used only 5 days instead of 20 days. Hence, it is possible that the series of pills may be less costly. On the other hand, the cost of packaging the sequential tablets may prohibit lowering the cost beyond a certain level. Furthermore, it must be emphasized that these pills must be taken in the proper sequence and this may produce a teaching problem in underdeveloped areas. From the physiological standpoint, it should be noted that the usual contraceptives of the combined tablet type are dependent upon three factors for preventing conception. These are, as previously indicated, ovulation inhibition, alteration in cervical mucous, and distortion of the endometrium. When the sequential approach is used, contraception is dependent entirely on inhibition of ovulation inasmuch as the other safeguards are not obtained with this method. Despite this, reports of studies are very encouraging.

Since it is possible that these contraceptive pills will be used for many years by some women in the next few decades, it is important that studies continue relative to possible long-term toxicity. In this connection, our clinic in Los Angeles is proceeding with detailed metabolic and blood chemistry studies on a relatively large scale which are intended to provide data on possible alterations in the function of the liver, adrenals, thyroid, pituitary, and other vital structures. We are also performing endometrial biopsies and Papanicolaou vaginal smears at relatively frequent intervals on all patients to help provide statistics on possible tumor-promoting effects of these agents. These data are being reported from time to time as they are tabulated.

SUMMARY

Oral contraception, after 9 years of use, has been shown to be a very effective method of voluntarily preventing pregnancy. It is very acceptable by patients, has aesthetic advantages over various methods of vaginal contraception, and is extremely effective. While there are still some questions as to the significance of certain side effects and the question of the relationship of more serious conditions to the use of the contraceptives, no evidence has appeared which would definitely incriminate these preparations as causative agents. It seems likely that the future will see expanding use of these preparations in the efforts at population control, but meanwhile, carefully controlled investigation must continue to probe into possible undiscovered deleterious effects.

* From the Planned Parenthood Centers of Los Angeles and The Tyler Clinic.
+ These studies were partly supported by G. D. Searle Co. f 921, Westwood Blvd., Los Angeles, Calif. 90024, U.S.A. 1141
1Some of the factors that we have studied in several dozen patients are: recalcitied dotting time, prothrombin: Quick and Owren, thromboplastin generation, platelets, euglobulin, cnoglobulin, plasminogen-plasmin, serum mucopolysaccharides, 24-hr urine mucopolysaaharides, and serum beta lipoprotein, and others.
2The Ad Hoc Committee for the Evaluation of a Possible Etiologic Relation with Thromboembolic
Conditions. Final Report on Enovid, submitted to the Commissioner of the Food and Drug Administration of the Department of Health, Education and Welfare, 12 Sept., 1963.
3 TYLER, E. T.: Oral contraception and venous thrombosis (Editorial), J. Am. med. Ass. 185, 131,
1963.
4 COOK, H. H., HAMBLE, C. J. and SATTEarawAlre, A. P.: Oral contraception by norethynodrel, Am. J. Obstet. Gynec. 82, 437, 1961; ECKSTEIN, P. et al.: Birmingham oral contraception trial, Br. med. J. 2, 1172, 1961; GOLDZIEHFR, J. W., MOSES, L. E. and EuLts, L. T.: Study of norethindrone in contraception, J. Am. med. Ass. 180, 359, 1962; PINCUS, G. et a7.: Effectiveness of oral contraception: effects of progestin-estrogen combination upon fertility, menstrual phenomena and health, Science 130, 81, 1959; PINCUS, G.: Field trials with norethynodrel as an oral contraceptive, Worcester Foundation publication; RICE-WRAY, E. et al.: Long-term administration of norethindrone in fertility control, J. Am. med. Ass. 180, 355, 1962; ROCK, J., GARCIA, C. R. and PINCUS, G.: Use of some progestational 19-nor steroids in gynecology, Am. J. Obsret. Gyltec. 79, 758, 1960; TYLER, E. T, and OLSON, H. J.: Fertility promoting and inhibiting effects of new steroid hormonal substances, J. Am. med. Ass. 169, 1843, 1959; TYLER, E. T. et al.: An oral contraception: 4-year study of norethindrone, Obstet. & Gynec. 18, 363, 1961.