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Long-Term Study of Oral Contraception with Norethindrone 2 mg. and Mestranol 0.1 mg.
Long-Term Study of Oral Contraception with Norethindrone 2 mg. and Mestranol 0.1 mg. W. POWELL HUTCHERSON, M.D., HAROLD A. SCHWARTZ, M.D., and WILLIAM WEATHERS, JR., M.D.
1956, when Rock and his associates established the ovulation-inhibiting properties of certain synthetic progestational substances, investigation of the effectiveness of these agents as oral contraceptives has gone steadily forward. In strong contrast to any controversy as to the mode of action of these drugs is the unanimous opinion as to their contraceptive efficacy. All clinical evidence derived from the use of the 2-mg. norethindrone and O.l-mg. mestranol tablet (Ortho-Novum 2 mg.*) points to the fact that even in this very low dosage the product loses none of its contraceptive efficacy.3-9 Qualitatively the incidental side effects with the 2-mg. tablet appear to resemble those seen with the 10-mg. tablet, but in the experience of those who have used both strengths, the incidence of breakthrough bleeding and nausea is sharply reduced with the lower dosage.a-6 Our initial experience with this particular dosage, encompassing a study of 306 women through a total of almost 2000 cycles, proved entirely satisfactory.a Substantial as this series was, it was felt nevertheless, that further conclusions should be based on as broad an experience as could be accumulated. Accordingly, our investigations have been continued and this report embodies the results obtained over a total period of study of more than 2% years.
SINCE
METHOD AND MATERIALS Patients
The study included patients from both private practice and from the planned parenthood clinic of a large general hospital. A total of 618 patients was observed; 347 were office patients and 271 were drawn from the clinic. From the Department of Obstetrics and Gynecology, Baroness Erlanger Hospital, Chattanooga, Tenn. *Ortho Pharmaceutical Corporation, Raritan, N. J. (Made available through the courtesy of Ortho Research Foundation.)
59
60
FERTILITY
HUTCHERSON ET AL.
& STERILITY
Only patients meeting certain rigidly applied criteria were admitted to the study. It was required that each patient be of proven fertility, be willing to practice contraception continuously for at least 1 year, and make herself available for regular breast and pelvic examinations. Moreover, it was required that the patient or a member of her family be able to read. In the early days of this study, care was also taken to exclude any patient in whom pregnancy might prove financially disastrous or a grave health hazard. The effectiveness of this contraceptive method no longer makes this factor a consideration. An analysis of the patients according to age and obstetric history is shown in Table 1. Duration of Treatment
The study has now been in progress for more than 2J6 years. Because of constant recruitment of new subjects and the high dropout rate unavoidable in this type of study, the treatment period has varied widely from patient to patient (Table 1). However, the private and clinic patients compare closely in both average duration and range of duration of treatment. Although average duration of treatment for the combined groups was 8.6 cycles, 187 patients (3'0.3%) remained under treatment 12 cycles or more; 97 (15.7%), 18 cycles or more; and 39 (6.3%), more than 24 cycles. Sixteen patients failed to complete 1 full cycle of treatment because of side reactions, phobias, and other miscellaneous reasons. In total, the study encompassed 533'0 cycles of treatment, representing more than 4'0'0 woman-years. Medication Procedure
The medication employed throughout the study consisted of tablets containing 2 mg. of norethindrone and '0.1 mg. of 3-methyl-ether ethinyl estradiol (mestranol). Before treatment, each patient was interviewed and given an explanation of the action of the drug as well as instruction as to its use.
TABLE 1. Age, Obstetric History, and Duration of Treatment of Patients Studied ~-------
Pre(m(mrie.~
A lie (yr.)
Patient.~
(No.) -----
StatuI!
Number
Rnnlle
At'.
Clinic Private
271 347 618
1.5-40 16-50 15-50
23.1 29.1 26.1
TOTAL
Total
975 8.59 1834
Children (No.)
-----
Trentment cJldeR
A'c.
Total
At'.
Total
Ranlle
A~'.
3.6 2.5 3.0
863 730 1593
3.2 2.1 2.6
1971 3359 5330
1-28 1-31 1-31
7..3 9.7 8.6
VOL.
17, No. 1,1966
2-MG. NORETHINDRONE
61
To make doubly sure of correct usage, written instructions were also supplied with the initial 2-month supply of the drug. Our regimen of treatment involved administration of one tablet daily from Day 5 through 25 of each cycle counting the first day of bleeding as Day 1, rather than from Day 5 through 24. This slight variation from the schedule used by other workers was adopted solely on the basis that the patient is less likely to become confused about dosage if instructed to take the drug for 21 days, or 3 weeks, rather than for 20 days. (Since July 1964, we have been using a 20-day treatment period because the tablets are packaged in bottles of 20.) It was recommended that the tablet be taken at bedtime, or with the largest meal of the day. Patients were further advised that menstruation would generally follow within 2 or 3 days of completing each course, but if menses did not occur, medication was to be resumed 7 days after the termination of the prior course. Patients who were started on the drug 6 weeks postpartum without an intervening menstrual period were advised to refrain from intercourse for the first 15 days of treatment, or to use an additional means of contraception during this period. All others were informed that protection against pregnancy would follow immediately on start of treatment. After starting treatment, all patients were instructed to return for breast and pelvic examination after completion of the first cycle of therapy, and thereafter every 3 months. Papanicolaou smears or acridine-orange smears were repeated every 6 months. RESULTS
No patient became pregnant while under treatment. This result, in line with that reported by others, provides further evidence of the apparently complete reliability of this contraceptive technic. Menstrual Flow
A slight decrease in menstrual How in women undergoing cyclic progestational therapy has been noted previously by several workers. In our experience it has proved particularly noticeable in patients with pre-existent menorrhagia. s In the present study, 34.8% of patients reported some diminution of menstrual volume, and only 3.2% indicated that they thought their How slightly heavier than formerly. There was, however, some disparity between clinic and private patients in effect on menses. Among the clinic patients, only 10% reported a diminution of menstrual volume, compared with 54.2% of private patients. None of the clinic patients reported increased volume, as compared with 5.7% of private patients.
62
HUTCHERSON ET AL.
FERTILITY
&
STERILITY
Breakthrough Bleedulg Slight intermenstrual bleeding or spotting is a relatively common accompaniment of cyclic progestational therapy. In this study, 127 (20.6%) of our 618 patients experienced bleeding episodes. However, in terms of cycles, only 327 (6.1%) of 5330 cycles were marked by intermenstrual bleeding. Such bleeding was observed by 65, slightly more than half of those noting any bleeding, during only 1 cycle. Among the remaining 62 who experienced more than one episode, only 17, less than 3% of all treated patients, noted bleeding in more than 4 cycles. Liability to bleeding was greatest during the first few cycles and diminished steadily as treatment progressed (Fig. 1). Thus, bleeding occurred in 6.8% of all patients in the first cycle, and in approximately 5.5% during the next 4 cycles. From the fifth month on, the incidence declined steadily, reaching entirely inconsequential proportions after the twelfth month. No significant difference was noted between clinic and private patients in their liability to this side effect. When bleeding occurred, it was generally confined to slight spotting and constituted no more than a minor inconvenience. 10.0 7.0 _
6.0
Fig. 1. Percentage of p a ti e n t s experiencing breakthrough bleeding, in relation to cycle of treatment.
5.0 -
4.0 ~
3 .. 0_
~
2.0 1.0
Cycle
1
2
3
4
5
6
7
8
9
10 11 12 13
Only 1 of the clinic and 2 of the private patients accounted it adequate reason for discontinuing treatment. In the beginning, we increased dosage to control breakthrough bleeding; at present, we reassure the patient and advise her to continue her schedule without alteration.
VOL. 17, No.1, 1966
2-MG. NORETHINDRONE
63
Weight Changes
A minor increase in weight is frequently observed in patients receiving cyclic progestational therapy. Weight records were maintained on 565 of our 618 patients (Table 2). Among these 565 patients, no change in weight was recorded in 114 (20%). Gain in weight was observed in 263 (46.5%) but in 128 (20.2%) the gain did not exceed 5 lb., and in only 46 (8.2%) did it exceed 10 lb. There were, nevertheless, 5 patients who gained more than 20 lb. in weight. We found no patient who could not control her weight if she used the usual dietary discretions in caloric intake. Only 1 patient who consistently gained weight ultimately withdrew from the study. Some loss in weight was recorded in 138 patients, representing 24.4% of the group. However, the loss did not exceed 5 lb. in 99 (17.5%) and in only 13 patients (2.3%) did it exceed 10 lb. There were 5 patients who lost 20 lb. or more. These patients had been treated with 1200-calorie diets, showing that patients receiving progestational therapy can actually lose weight if they adhere to prescribed diets; no patient lost weight during this study unless she deliberately dieted. Thus, in total, weight gain was recorded twice as frequently as weight loss. This finding conforms with the experience of others and suggests that cyclic progestational medication can produce weight gain through its general anabolic properties, by causing fluid retention, or possibly by a combination of these and other factors. Other Side Effects
The incidence of side reactions has been gratifyingly low (Table 3). The most frequent complaint was nausea, this reaction being reported by 18 (2.9%) of the 618 patients. Predominantly this reaction occurred in the first month and usually had disappeared by the end of the second month. Nausea was generally mild and most noticeable in the mornings. In only a few instances was it accompanied by actual vomiting. Breast enlargement and/or TABLE 2. Distribution of Weight Changes During Treatment Gain II
TV eight (lb.)
0-5 5-10 10-15 15-20 Over 20 TOTAL
I
l_
L088
No.
%
No.
%
128 89 36 5 5 263
20.2 15.7 6.4 0.9 0.9 44.1
99 26 4 4 5 138
17.5 4.6 0.7 0.7 0.9 24.4
64
HUTCHERSON ET AL.
FERTILITY & STERILITY
TABLE 3. Distribution of Side Reactions Exclusive of Breakthrough Bleeding and Weight Gain Complaining Reaction
No.
%
Leav'ing study
Nausea Mastalgia Nervousness Fatigue Headaches Decreased libido Facial hirsutism Dysmenorrhea Amenorrhea General malaise Miscellaneous TOTAL
18 10 8 7 7 5 3
2.9
7 2
3
3 2 13 79
1.6 1.3 1.1
4 2
1.1
0.8 0.5 0.5 0.5 0.3 2.1 12.7
3 1 1 1 2 7 30 (48%)
tenderness was the second most frequent complaint, occurring in 10 (1.6%). A feeling of "nervousness" was reported by 8 (1.3%). Fatigue and headaches were reported by 7 (1.1%) each, and decreased libido by 5 (0.8%). Three patients complained of increased hair growth on the face, confined to a slight growth of hair on the upper lip and sides of the face. The hair growth was negligible, if any, as estimated by us. Only 1 felt it sufficiently disfiguring to justify discontinuance of treatment. Three patients complained of dysmenorrhea, a somewhat paradoxical finding insofar as a number of patients who had previously suffered from dysmenorrhea sustained complete or almost complete relief from cyclic progestin therapy. Miscellaneous complaints included one case each of nipple discharge, dryness of skin, allergic reaction, edema, chloasma, abdominal cramps, aggrava·· tion of hay fever, diarrhea, pelvic pain, pain in the right lower quadrant, premenstrual rash, premenstrual backache, and "feeling fainty." There was, surprisingly, a noteworthy difference between clinic and private patients in the incidence of recorded side reactions. Among clinic patients, only 28 ( 10.3%) were recorded as complaining of side effects. Among office patients, 51 (14.7%) voiced such complaints, an incidence almost one-and-a-half times that prevailing among the clinic patients. Discontinuance of Therapy
Thirty patients discontinued the drug because of the side reactions listed above. If to these 30 are added 3 patients who discontinued because of breakthrough bleeding, and 1 who stopped therapy because of excessive
VOL.
17, No. 1,1966
2-MG. NORETHINDRONE
65
weight gain, a total of 34 patients terminated h"eatment for reasons ostensibly attributable to medication. This represents a dropout rate for drug reasons of only 5.5%. Again, there was a notable discrepancy between private and clinic patients in withdrawal from study for drug reasons. Only 2 (0.7%) among 271 clinic patients withdrew for such reasons, whereas 32 (9.2%) of 347 private patients elected to terminate therapy for reasons attributable to medication. A substantially larger number of patients withdrew from the study, after varying periods of treatment, for reasons unconnected with the drug. These women were motivated to withdraw by desire to become pregnant, death of husband, divorce, removal from community, and similar reasons. In this category, the dropout rate was higher for clinic than for private patients (85, 31.4%, and 30, 8.6%, respectively). In all, 87 (32.1%) of 271 clinic and 62 (17.8%) of 347 private patients withdrew, a total of 149 patients or 24.1% of the entire study group. Laboratory Tests
Fifty patients were chosen at random for a wide range of laboratory tests, with the object of uncovering any asymptomatic toxicity. Differential blood counts and urinalyses after periods of treatment ranging from 4 to 1.5 cycles revealed no abnormality. At the same time, a battery of other laboratory examinations was performed, to test the functions of the thyroid, parathyroid, kidney, adrenals, liver, and pancreas. Bromosulfophthalein retention was slightly increased in 11 patients (22%). Protein-bound iodine was increased in 22 (44%). Calcium, fibrinogen, and cholesterol were markedly increased in 1 patient each. The patient whose cholesterol level was elevated has since been found to have a hypercholesterolemic mother. Fasting blood sugar was increased in a known diabetic. Phosphorus was decreased in 3 patients (6%). Other tests performed included BUN, SCOT, and alkaline phosphatase determinations. Except for the 1 case of increased fibrinogen, no evidence of interference with the normal mechanisms of blood coagulation could be found. To check clotting factors, calcium, fibrinogen, prothrombin time, clotting time, and partial thromboplastin time were determined, platelets estimated, and clot retraction observed. DISCUSSION
~
,
The clinical experience reported above, encompassing treatment of 618 women through a total of 5330 cycles, has served to corroborate the findings reported previously after a more limited clinical triaP That complete
66
HUTCHERSON ET AL.
FEHTILITY
& STEHlLlTY
protection against pregnancy was enjoyed by all patients in this series taking the medication as prescribed is fully in agreement with the findings of other workers. This combined evidence now provides adequate ground for regarding the administration of norethindrone 2 mg. with mestranol 0.1 mg. on the described cyclic basis as a contraceptive measure of virtually 100% reliability. In this series of cases, the incidence of side reactions has been gratifyingly low. Even nausea, the reaction occurring with greatest frequency in patients receiving cyclic progestin therapy, was seen in less than 3% of our cases. Breathrough bleeding or spotting has occurred in approximately one-fifth of our patients. Its relative unimportance, however, may be gauged from the fact that only 3 patients felt sufficiently disturbed by its appearance to stop treatment. Both nausea and breakthrough bleeding were largely confined to the first four months of treatment, tending to disappear spontaneously as therapy was continued beyond this point. The incidence (20.6%) of breakthrough bleeding observed by us corresponds closely with that reported by Ringrose and by Newland and associates, but is still greater than that recorded by Tyler and by Beer, who report incidences of 10 and 4%, respectively. Our observed incidence of nausea (2.9%) is less than that of the workers mentioned above. A minor weight gain was seen in a significant percentage of our cases and substantial weight gain was observed in a few. Again, the extent of the problem may be measured by the fact that only 1 patient discontinued therapy for this reason, while 18 patients (2.3%) lost 10 lb. or more, and 5 lost 20 lb. when adhering to a restricted 1200-calorie diet. The general acceptability of the therapy has been attested by the small percentage of patients (5.5%) withdrawing from the study for reasons associated with the drug. It has been further fortified by the spontaneous comments of many of the patients who, almost without exception, expressed an overwhelming preference for the oral contraceptive method over the mechanical methods previouslv employed. In addition, most women of the premenopausal age group, with the beginning of irregularity of cycles, premenstrual tension, nervousness, and flushes, found the medication a "godsend." Some difference was noted between clinic and private patients, both in the reported incidence of side reactions, and in their tendencies to withdraw from the study for reasons unrelated to the drug. The greater frequency of complaints of drug reactions among private patients may be attributable to greater sensitivity to minor discomforts than shown by the less privileged clinic patients. On the other hand, the greater tendency of clinic
\'OL. 17, :\0. 1, 1966
2-~IG.
;\I on ETHl:'> Dno:'> E
67
patients to withdraw from the study for reasons unconnected with the drug may well reflect, among other things, a more nomadic existence, a more frequent disruption of husband-wife relationships, and less stability of intent in family planning.
SUMMARY Tablets containing 2 mg. of norethindrone and 0.1 mg. of mestranol were administered on a cyclic basis to 618 patients for varying periods, to a maximum of 31 menstrual cycles. During the period of administration, no patient became pregnant while taking these tablets as prescribed. Side effects were sufficiently mild and infrequent as to cause a medication-connected dropout rate of only 5.5%. Experience accumulated over 2~~ years of clinical trial indicated that these tablets administered on the prescribed cyclic basis provide a safe method of oral contraception of virtually complete reliability. 744 McCallie Ave. Chattanooga, Tenn.
REFERENCES 1. BEER, M. A. Contraceptive efficacy of norethindrone in new low dosage form (Ortho-Novum 2 mg.). J. M. Soc. New Jersey 61:449,1964. 2. GOLDZIEHER, J. W. Newer drugs in oral contraception. Med. Clin. N. Amer. 49: 529,1964. 3. HUTCHERSON, W. P., SCHWARTZ, H. A., and SMITH, L. Norethindrone with estrogen as an oral contraceptive: A preliminary report. South. M. ]. 56:1357, 1963. 4. KRUEGER, H. G., and SANDERS, J. H. Experience in private practice with norethindrone and mestranol (Ortho-N ovum 2 mg.), a new low dosage oral contraceptive. Ohio M. ]. 60:548, 1964. 5. NEWLAND, D.O., et aZ. Effectiveness of a low dosage oral contraceptive tabletnorethindrone 2 mg. with 0.1 mg. mestranol. Obst. & Gynec. 23:920, 1964. 6. RINGROSE, C. A. D. Current concepts in conception control. Canad. M. A. ]. 89: 246, 1963. 7. ROCK, J., PINCUS, G., and GARCIA, C. R. Effects of certain 19-nor steroids on the normal human menstrual cycle. Science 124:891, 1956. 8. STATZER, D. Norethindrone 2 mg. and mestranol 0.1 mg. (Ortho-Novum 2 mg.): An evaluation of effectiveness in control of conception. Unpublished data. 9. TYLER, E. T. Current status of oral contraception. ].A.M.A. 187:562, 1964. 10. WEARING, M. P. The use of norethindrone 2 mg. with 0.1 mg. mestranol in fertility control. Canad. M. A. J. 89:239, 1963.
1956, when Rock and his associates established the ovulation-inhibiting properties of certain synthetic progestational substances, investigation of the effectiveness of these agents as oral contraceptives has gone steadily forward. In strong contrast to any controversy as to the mode of action of these drugs is the unanimous opinion as to their contraceptive efficacy. All clinical evidence derived from the use of the 2-mg. norethindrone and O.l-mg. mestranol tablet (Ortho-Novum 2 mg.*) points to the fact that even in this very low dosage the product loses none of its contraceptive efficacy.3-9 Qualitatively the incidental side effects with the 2-mg. tablet appear to resemble those seen with the 10-mg. tablet, but in the experience of those who have used both strengths, the incidence of breakthrough bleeding and nausea is sharply reduced with the lower dosage.a-6 Our initial experience with this particular dosage, encompassing a study of 306 women through a total of almost 2000 cycles, proved entirely satisfactory.a Substantial as this series was, it was felt nevertheless, that further conclusions should be based on as broad an experience as could be accumulated. Accordingly, our investigations have been continued and this report embodies the results obtained over a total period of study of more than 2% years.
SINCE
METHOD AND MATERIALS Patients
The study included patients from both private practice and from the planned parenthood clinic of a large general hospital. A total of 618 patients was observed; 347 were office patients and 271 were drawn from the clinic. From the Department of Obstetrics and Gynecology, Baroness Erlanger Hospital, Chattanooga, Tenn. *Ortho Pharmaceutical Corporation, Raritan, N. J. (Made available through the courtesy of Ortho Research Foundation.)
59
60
FERTILITY
HUTCHERSON ET AL.
& STERILITY
Only patients meeting certain rigidly applied criteria were admitted to the study. It was required that each patient be of proven fertility, be willing to practice contraception continuously for at least 1 year, and make herself available for regular breast and pelvic examinations. Moreover, it was required that the patient or a member of her family be able to read. In the early days of this study, care was also taken to exclude any patient in whom pregnancy might prove financially disastrous or a grave health hazard. The effectiveness of this contraceptive method no longer makes this factor a consideration. An analysis of the patients according to age and obstetric history is shown in Table 1. Duration of Treatment
The study has now been in progress for more than 2J6 years. Because of constant recruitment of new subjects and the high dropout rate unavoidable in this type of study, the treatment period has varied widely from patient to patient (Table 1). However, the private and clinic patients compare closely in both average duration and range of duration of treatment. Although average duration of treatment for the combined groups was 8.6 cycles, 187 patients (3'0.3%) remained under treatment 12 cycles or more; 97 (15.7%), 18 cycles or more; and 39 (6.3%), more than 24 cycles. Sixteen patients failed to complete 1 full cycle of treatment because of side reactions, phobias, and other miscellaneous reasons. In total, the study encompassed 533'0 cycles of treatment, representing more than 4'0'0 woman-years. Medication Procedure
The medication employed throughout the study consisted of tablets containing 2 mg. of norethindrone and '0.1 mg. of 3-methyl-ether ethinyl estradiol (mestranol). Before treatment, each patient was interviewed and given an explanation of the action of the drug as well as instruction as to its use.
TABLE 1. Age, Obstetric History, and Duration of Treatment of Patients Studied ~-------
Pre(m(mrie.~
A lie (yr.)
Patient.~
(No.) -----
StatuI!
Number
Rnnlle
At'.
Clinic Private
271 347 618
1.5-40 16-50 15-50
23.1 29.1 26.1
TOTAL
Total
975 8.59 1834
Children (No.)
-----
Trentment cJldeR
A'c.
Total
At'.
Total
Ranlle
A~'.
3.6 2.5 3.0
863 730 1593
3.2 2.1 2.6
1971 3359 5330
1-28 1-31 1-31
7..3 9.7 8.6
VOL.
17, No. 1,1966
2-MG. NORETHINDRONE
61
To make doubly sure of correct usage, written instructions were also supplied with the initial 2-month supply of the drug. Our regimen of treatment involved administration of one tablet daily from Day 5 through 25 of each cycle counting the first day of bleeding as Day 1, rather than from Day 5 through 24. This slight variation from the schedule used by other workers was adopted solely on the basis that the patient is less likely to become confused about dosage if instructed to take the drug for 21 days, or 3 weeks, rather than for 20 days. (Since July 1964, we have been using a 20-day treatment period because the tablets are packaged in bottles of 20.) It was recommended that the tablet be taken at bedtime, or with the largest meal of the day. Patients were further advised that menstruation would generally follow within 2 or 3 days of completing each course, but if menses did not occur, medication was to be resumed 7 days after the termination of the prior course. Patients who were started on the drug 6 weeks postpartum without an intervening menstrual period were advised to refrain from intercourse for the first 15 days of treatment, or to use an additional means of contraception during this period. All others were informed that protection against pregnancy would follow immediately on start of treatment. After starting treatment, all patients were instructed to return for breast and pelvic examination after completion of the first cycle of therapy, and thereafter every 3 months. Papanicolaou smears or acridine-orange smears were repeated every 6 months. RESULTS
No patient became pregnant while under treatment. This result, in line with that reported by others, provides further evidence of the apparently complete reliability of this contraceptive technic. Menstrual Flow
A slight decrease in menstrual How in women undergoing cyclic progestational therapy has been noted previously by several workers. In our experience it has proved particularly noticeable in patients with pre-existent menorrhagia. s In the present study, 34.8% of patients reported some diminution of menstrual volume, and only 3.2% indicated that they thought their How slightly heavier than formerly. There was, however, some disparity between clinic and private patients in effect on menses. Among the clinic patients, only 10% reported a diminution of menstrual volume, compared with 54.2% of private patients. None of the clinic patients reported increased volume, as compared with 5.7% of private patients.
62
HUTCHERSON ET AL.
FERTILITY
&
STERILITY
Breakthrough Bleedulg Slight intermenstrual bleeding or spotting is a relatively common accompaniment of cyclic progestational therapy. In this study, 127 (20.6%) of our 618 patients experienced bleeding episodes. However, in terms of cycles, only 327 (6.1%) of 5330 cycles were marked by intermenstrual bleeding. Such bleeding was observed by 65, slightly more than half of those noting any bleeding, during only 1 cycle. Among the remaining 62 who experienced more than one episode, only 17, less than 3% of all treated patients, noted bleeding in more than 4 cycles. Liability to bleeding was greatest during the first few cycles and diminished steadily as treatment progressed (Fig. 1). Thus, bleeding occurred in 6.8% of all patients in the first cycle, and in approximately 5.5% during the next 4 cycles. From the fifth month on, the incidence declined steadily, reaching entirely inconsequential proportions after the twelfth month. No significant difference was noted between clinic and private patients in their liability to this side effect. When bleeding occurred, it was generally confined to slight spotting and constituted no more than a minor inconvenience. 10.0 7.0 _
6.0
Fig. 1. Percentage of p a ti e n t s experiencing breakthrough bleeding, in relation to cycle of treatment.
5.0 -
4.0 ~
3 .. 0_
~
2.0 1.0
Cycle
1
2
3
4
5
6
7
8
9
10 11 12 13
Only 1 of the clinic and 2 of the private patients accounted it adequate reason for discontinuing treatment. In the beginning, we increased dosage to control breakthrough bleeding; at present, we reassure the patient and advise her to continue her schedule without alteration.
VOL. 17, No.1, 1966
2-MG. NORETHINDRONE
63
Weight Changes
A minor increase in weight is frequently observed in patients receiving cyclic progestational therapy. Weight records were maintained on 565 of our 618 patients (Table 2). Among these 565 patients, no change in weight was recorded in 114 (20%). Gain in weight was observed in 263 (46.5%) but in 128 (20.2%) the gain did not exceed 5 lb., and in only 46 (8.2%) did it exceed 10 lb. There were, nevertheless, 5 patients who gained more than 20 lb. in weight. We found no patient who could not control her weight if she used the usual dietary discretions in caloric intake. Only 1 patient who consistently gained weight ultimately withdrew from the study. Some loss in weight was recorded in 138 patients, representing 24.4% of the group. However, the loss did not exceed 5 lb. in 99 (17.5%) and in only 13 patients (2.3%) did it exceed 10 lb. There were 5 patients who lost 20 lb. or more. These patients had been treated with 1200-calorie diets, showing that patients receiving progestational therapy can actually lose weight if they adhere to prescribed diets; no patient lost weight during this study unless she deliberately dieted. Thus, in total, weight gain was recorded twice as frequently as weight loss. This finding conforms with the experience of others and suggests that cyclic progestational medication can produce weight gain through its general anabolic properties, by causing fluid retention, or possibly by a combination of these and other factors. Other Side Effects
The incidence of side reactions has been gratifyingly low (Table 3). The most frequent complaint was nausea, this reaction being reported by 18 (2.9%) of the 618 patients. Predominantly this reaction occurred in the first month and usually had disappeared by the end of the second month. Nausea was generally mild and most noticeable in the mornings. In only a few instances was it accompanied by actual vomiting. Breast enlargement and/or TABLE 2. Distribution of Weight Changes During Treatment Gain II
TV eight (lb.)
0-5 5-10 10-15 15-20 Over 20 TOTAL
I
l_
L088
No.
%
No.
%
128 89 36 5 5 263
20.2 15.7 6.4 0.9 0.9 44.1
99 26 4 4 5 138
17.5 4.6 0.7 0.7 0.9 24.4
64
HUTCHERSON ET AL.
FERTILITY & STERILITY
TABLE 3. Distribution of Side Reactions Exclusive of Breakthrough Bleeding and Weight Gain Complaining Reaction
No.
%
Leav'ing study
Nausea Mastalgia Nervousness Fatigue Headaches Decreased libido Facial hirsutism Dysmenorrhea Amenorrhea General malaise Miscellaneous TOTAL
18 10 8 7 7 5 3
2.9
7 2
3
3 2 13 79
1.6 1.3 1.1
4 2
1.1
0.8 0.5 0.5 0.5 0.3 2.1 12.7
3 1 1 1 2 7 30 (48%)
tenderness was the second most frequent complaint, occurring in 10 (1.6%). A feeling of "nervousness" was reported by 8 (1.3%). Fatigue and headaches were reported by 7 (1.1%) each, and decreased libido by 5 (0.8%). Three patients complained of increased hair growth on the face, confined to a slight growth of hair on the upper lip and sides of the face. The hair growth was negligible, if any, as estimated by us. Only 1 felt it sufficiently disfiguring to justify discontinuance of treatment. Three patients complained of dysmenorrhea, a somewhat paradoxical finding insofar as a number of patients who had previously suffered from dysmenorrhea sustained complete or almost complete relief from cyclic progestin therapy. Miscellaneous complaints included one case each of nipple discharge, dryness of skin, allergic reaction, edema, chloasma, abdominal cramps, aggrava·· tion of hay fever, diarrhea, pelvic pain, pain in the right lower quadrant, premenstrual rash, premenstrual backache, and "feeling fainty." There was, surprisingly, a noteworthy difference between clinic and private patients in the incidence of recorded side reactions. Among clinic patients, only 28 ( 10.3%) were recorded as complaining of side effects. Among office patients, 51 (14.7%) voiced such complaints, an incidence almost one-and-a-half times that prevailing among the clinic patients. Discontinuance of Therapy
Thirty patients discontinued the drug because of the side reactions listed above. If to these 30 are added 3 patients who discontinued because of breakthrough bleeding, and 1 who stopped therapy because of excessive
VOL.
17, No. 1,1966
2-MG. NORETHINDRONE
65
weight gain, a total of 34 patients terminated h"eatment for reasons ostensibly attributable to medication. This represents a dropout rate for drug reasons of only 5.5%. Again, there was a notable discrepancy between private and clinic patients in withdrawal from study for drug reasons. Only 2 (0.7%) among 271 clinic patients withdrew for such reasons, whereas 32 (9.2%) of 347 private patients elected to terminate therapy for reasons attributable to medication. A substantially larger number of patients withdrew from the study, after varying periods of treatment, for reasons unconnected with the drug. These women were motivated to withdraw by desire to become pregnant, death of husband, divorce, removal from community, and similar reasons. In this category, the dropout rate was higher for clinic than for private patients (85, 31.4%, and 30, 8.6%, respectively). In all, 87 (32.1%) of 271 clinic and 62 (17.8%) of 347 private patients withdrew, a total of 149 patients or 24.1% of the entire study group. Laboratory Tests
Fifty patients were chosen at random for a wide range of laboratory tests, with the object of uncovering any asymptomatic toxicity. Differential blood counts and urinalyses after periods of treatment ranging from 4 to 1.5 cycles revealed no abnormality. At the same time, a battery of other laboratory examinations was performed, to test the functions of the thyroid, parathyroid, kidney, adrenals, liver, and pancreas. Bromosulfophthalein retention was slightly increased in 11 patients (22%). Protein-bound iodine was increased in 22 (44%). Calcium, fibrinogen, and cholesterol were markedly increased in 1 patient each. The patient whose cholesterol level was elevated has since been found to have a hypercholesterolemic mother. Fasting blood sugar was increased in a known diabetic. Phosphorus was decreased in 3 patients (6%). Other tests performed included BUN, SCOT, and alkaline phosphatase determinations. Except for the 1 case of increased fibrinogen, no evidence of interference with the normal mechanisms of blood coagulation could be found. To check clotting factors, calcium, fibrinogen, prothrombin time, clotting time, and partial thromboplastin time were determined, platelets estimated, and clot retraction observed. DISCUSSION
~
,
The clinical experience reported above, encompassing treatment of 618 women through a total of 5330 cycles, has served to corroborate the findings reported previously after a more limited clinical triaP That complete
66
HUTCHERSON ET AL.
FEHTILITY
& STEHlLlTY
protection against pregnancy was enjoyed by all patients in this series taking the medication as prescribed is fully in agreement with the findings of other workers. This combined evidence now provides adequate ground for regarding the administration of norethindrone 2 mg. with mestranol 0.1 mg. on the described cyclic basis as a contraceptive measure of virtually 100% reliability. In this series of cases, the incidence of side reactions has been gratifyingly low. Even nausea, the reaction occurring with greatest frequency in patients receiving cyclic progestin therapy, was seen in less than 3% of our cases. Breathrough bleeding or spotting has occurred in approximately one-fifth of our patients. Its relative unimportance, however, may be gauged from the fact that only 3 patients felt sufficiently disturbed by its appearance to stop treatment. Both nausea and breakthrough bleeding were largely confined to the first four months of treatment, tending to disappear spontaneously as therapy was continued beyond this point. The incidence (20.6%) of breakthrough bleeding observed by us corresponds closely with that reported by Ringrose and by Newland and associates, but is still greater than that recorded by Tyler and by Beer, who report incidences of 10 and 4%, respectively. Our observed incidence of nausea (2.9%) is less than that of the workers mentioned above. A minor weight gain was seen in a significant percentage of our cases and substantial weight gain was observed in a few. Again, the extent of the problem may be measured by the fact that only 1 patient discontinued therapy for this reason, while 18 patients (2.3%) lost 10 lb. or more, and 5 lost 20 lb. when adhering to a restricted 1200-calorie diet. The general acceptability of the therapy has been attested by the small percentage of patients (5.5%) withdrawing from the study for reasons associated with the drug. It has been further fortified by the spontaneous comments of many of the patients who, almost without exception, expressed an overwhelming preference for the oral contraceptive method over the mechanical methods previouslv employed. In addition, most women of the premenopausal age group, with the beginning of irregularity of cycles, premenstrual tension, nervousness, and flushes, found the medication a "godsend." Some difference was noted between clinic and private patients, both in the reported incidence of side reactions, and in their tendencies to withdraw from the study for reasons unrelated to the drug. The greater frequency of complaints of drug reactions among private patients may be attributable to greater sensitivity to minor discomforts than shown by the less privileged clinic patients. On the other hand, the greater tendency of clinic
\'OL. 17, :\0. 1, 1966
2-~IG.
;\I on ETHl:'> Dno:'> E
67
patients to withdraw from the study for reasons unconnected with the drug may well reflect, among other things, a more nomadic existence, a more frequent disruption of husband-wife relationships, and less stability of intent in family planning.
SUMMARY Tablets containing 2 mg. of norethindrone and 0.1 mg. of mestranol were administered on a cyclic basis to 618 patients for varying periods, to a maximum of 31 menstrual cycles. During the period of administration, no patient became pregnant while taking these tablets as prescribed. Side effects were sufficiently mild and infrequent as to cause a medication-connected dropout rate of only 5.5%. Experience accumulated over 2~~ years of clinical trial indicated that these tablets administered on the prescribed cyclic basis provide a safe method of oral contraception of virtually complete reliability. 744 McCallie Ave. Chattanooga, Tenn.
REFERENCES 1. BEER, M. A. Contraceptive efficacy of norethindrone in new low dosage form (Ortho-Novum 2 mg.). J. M. Soc. New Jersey 61:449,1964. 2. GOLDZIEHER, J. W. Newer drugs in oral contraception. Med. Clin. N. Amer. 49: 529,1964. 3. HUTCHERSON, W. P., SCHWARTZ, H. A., and SMITH, L. Norethindrone with estrogen as an oral contraceptive: A preliminary report. South. M. ]. 56:1357, 1963. 4. KRUEGER, H. G., and SANDERS, J. H. Experience in private practice with norethindrone and mestranol (Ortho-N ovum 2 mg.), a new low dosage oral contraceptive. Ohio M. ]. 60:548, 1964. 5. NEWLAND, D.O., et aZ. Effectiveness of a low dosage oral contraceptive tabletnorethindrone 2 mg. with 0.1 mg. mestranol. Obst. & Gynec. 23:920, 1964. 6. RINGROSE, C. A. D. Current concepts in conception control. Canad. M. A. ]. 89: 246, 1963. 7. ROCK, J., PINCUS, G., and GARCIA, C. R. Effects of certain 19-nor steroids on the normal human menstrual cycle. Science 124:891, 1956. 8. STATZER, D. Norethindrone 2 mg. and mestranol 0.1 mg. (Ortho-Novum 2 mg.): An evaluation of effectiveness in control of conception. Unpublished data. 9. TYLER, E. T. Current status of oral contraception. ].A.M.A. 187:562, 1964. 10. WEARING, M. P. The use of norethindrone 2 mg. with 0.1 mg. mestranol in fertility control. Canad. M. A. J. 89:239, 1963.