Side Effects of Cyclic Therapy with Norethindrone and Mestranol

Side Effects of Cyclic Therapy with Norethindrone and Mestranol BERYL A. CHERNICK, M.D. *

of conception control in Western countries and the even greater importance of limiting the population explosion in the underdeveloped countries are almost universally recognized. At present, there is no doubt that using the progestational steroids in a cyclic fashion is the most reliable method of conception control known. In August 1961, clinical studies began here of the effects of cyclic therapy with tablets containing norethindrone (5 mg.) and mestranol (75 p,g.) (Ortho-Novum). t General acceptability and side effects during the first year of use have been reported. 7 Since then, our attention has turned from the usual side effects of estrogen-progestin compounds, nausea and breakthrough bleeding, to others which have become more prominent. Patients are now being observed for signs and symptoms likely to be due to water retention, especially weight gain, elevation of blood pressure, and depression. Certain parameters are being followed and further tests are planned for more thorough investigation. This report presents preliminary findings.

THE IMPORTANCE

MATERIAL AND METHODS

The composition of the population in the study is shown below. Presenting New patients

Clinic

Private

221 31

52

o

From the Departments of Obstetrics and Gynaecology and of Pharmacology, University of Western Ontario, London, Ont., Canada. Presented at the lIth Annual Meeting of the Canadian Society for the Study of Fertility, Vancouver, B. C., Canada, June 17 and 18, 1!J64. Supported in part by a grant-in-aid from Ortho Pharmaceutical (Canada) Ltd. The author is indebted to Dr. J. 'V. D. Cornett, for aid in this research, to Professor R. A. H. Kinch for making available his patients and facilities and for his guidance and encouragement, and to the Nursing Staff of the Victoria Hospital Outpatient Department, London, Canada, for their cooperation. *Fellow of the Medical Research Council of Canada. tOrtho Pharmaceutical (Canada) Ltd., Don Mills, Ont., Canada.

445

446

CHERNICK

Discontinued Did not return Corrected total Cycles

FERTILITY

&

STERILITY

45 31

30

114

22 786

1907

o

Two main groups of patients are being followed and the data for each are presented separately. Clinic patients were 221 women referred to this clinic for Ortho-Novum therapy in the past 2~~ years. Of these, 76 have been lost to the study: 31 never returned to the clinic and 45 discontinued the medication for a variety of reasons. Because many of these patients discontinued treatment before we were interested in their blood pressure and emotional responses, the data for these women are omitted. There are 145 women now attending this weekly clinic. Of these, 31 are new patients who have not yet paid their first return visit to the clinic. There remain 114 clinic patients under careful observation. Of the 52 private patients, 30 discontinued the medication. Because of the size of this group and because similar data are available for both active and discontinued patients, all 52 were included in the study. All patients took the 5-mg. Ortho-Novum tablet daily, from Day 5 to Day 24 or 25 inclusive for 1-30 cycles. The clinic patients completed a total of 1907 cycles, including 458 cycles completed by the 45 patients who later discontinued the medication. The private patients completed 786 cycles, including 346 cycles completed by those who later discontinued the medication. The clinic patients were usually seen at 3-month intervals whereas the private patients were usually seen every 6 months. Only 16 patients in the study took the medication for a primary indication other than contraception. RESULTS

No patient who followed instructions became pregnant while on therapy. The age distribution of the clinic and private patients was comparable. There were more younger women in the cliuic group and more older women in the private group (Fig. 1). There was a marked difference in the number of pregnancies per patient before medication; the clinic group had far greater parity than the private group (Table 1). The side effects studied in detail were weight gain, hypertension, and emotional disturbances. Weight gain was arbitrarily defined as a gain of 5 lb. or more while on therapy. In many cases, a gradual gain of 10--15 pounds occurred during the first 3 or 4 cycles. The weight remained relatively stable at this higher level despite efforts at dieting. Various anorexic

VOL. 16, No.4, 1965

447

ESTROGEN-PROGESTIN SIDE EFFECTS

pills were given, on request, to 38% of the clinic patients, usually in addition to dietetic advice from the hospital dietician. This therapy resulted in loss of weight in only a few of these patients. Only when the patient discontinued the Ortho-Novum therapy did she lose this excess weight. Weight gain is such a common side effect of Ortho-Novum therapy, that it is a major deterrent to the private patient who may be considering adopting this method of contraception. Many of the new clinic patients were well aware of the possibility of this weight gain. Their appearance at the clinic showed that, for them, the infallibility of the medication as a contraceptive far outweighed this disadvantage. Women who did complain of gaining uncomplimentary pounds were reminded that they were free to stop taking the pills whenever they chose and that they would be given a reliable contraceptive substitute if desired. They replied that they "wouldn't stop the pills for anything and even if they would, their husbands wouldn't II CLINIC-215 •

Fig. 1. Age distribution of clinic and private patients.

PRIVATE- 50

... .....,oz

..,ua: IL

AGE

TABLE l. Parity of 215 Clinic and 50 Private Patients Before Medication Patients (%) Pregnancies

0 1 2 3 4 5 6 7 8+ TOTAL

Clinic

0.5 3.7 12 ..5 13.8 15.7 14.8 11.4 10.4 18.1 1115

pJ'ivate

14 22 20 22 16 2 2 2 0 114

448

FERTILITY

CHERNICK

& STERILITY

let them." Unfortunately the 90- or lOO-lb. chronically underweight girl desirous of gaining a few pounds rarely succeeds while taking Ortho-Novum. Some of the patients who did not have a steady weight increase showed a cyclic gain of 3-5 lb. in the last few days of the cycle and lost this weight 60

60

A-ACTIVE CLiNIC-114 B-ALL PRIVATE-52

A - ACTIVE CLINIC - 114 B - PRIVATE - 52

~ WEIGHT GAIN

50

50 •

WEIGHT GAIN PLUS BLOATING, ETC.

I:.'i!I RECORDED BLOOD PRESSURE Ii:lllI ELEVATION


I
40

I-

....

i

~ 40

I-

Z

30

.... o

~ ~ 30

•

RECORDED BLOOD PRESSURE ELEVATION PLUS VASCULAR HEADACHE

!z.... u

I-

~ 20

u

a: ....

"- 10

o

IS

20

"10

B O A

Fig. 2 (left). Incidence of weight gain and water retention during therapy. Fig. 3 (right). Incidence of recorded blood-pressure elevation and vascular headache during therapy.

by the end of the menstrual period. Others gained weight at the end of each cycle and proceeded to a stepwise increase of 10-15 lb. This weight gain in the latter part of the cycle was accompanied by bloating of the abdomen with or without facial and finger swelling, and pitting edema of the legs, suggestive of tissue water retention (Fig. 2). Patients who had had premenstrual bloating before taking Ortho-Novum, and who also had it while on therapy, complained of bloating throughout the cycle rather than just premenstrually. Symptomatic relief resulted when diuretics were prescribed during the latter half of the cycle. Figure 3 depicts the percentage of patients in whom an elevation of blood pressure was recorded while they were taking Ortho-Novum. The criteria for an elevation of blood pressure were arbitrarily chosen as those defined for toxemia of pregnancy,5 i.e., a systolic blood pressure of 140 mm. Hg or more, or a rise of 30 mm. or more above the usual level, or a diastolic pressure of 90 mm. or more, or a rise of 15 mm. or more above the usual level. Blood-pressure readings were recorded most frequently for the active clinic patients; this group showed the highest incidence of elevated blood-pressure readings. Many of the patients included in this category had an elevation at only one reading, but in the entire series 20 patients had definite elevations from their usual readings of about 110/70 during the

11 •

VOL.

16, No.4, 1965

E~TROGEN-PROGESTIN SIDE EFFECTS

449

first few months of therapy, to readings of about 140-150/lO0 on later occasions. Blood pressure returned to normal if the medication was discontinued, and in some cases, even while medication was continued. About 20% of each group claimed to have some headaches at some time between Day 24 and Day 5 of the following cycle. From the descriptions, the headache is a typically vascular type. It is likely that this headache is symptomatic of the hypertension. One of the private patients was seen on Day 26 of her cycle while experiencing a severe pounding frontal headache unrelieved by the usual analgesics. She had noticed a weight gain of 3 lb. in the past 2 days. That morning her eyelids were puffy and her fingers so swollen that she could not remove her rings. Blood-pressure readings at 3-hr. intervals revealed a pressure of 145/90-much above her usual level. Tests of the urine at this time revealed a 1+ albuminuria. A diuretic relieved the headache and the blood pressure returned to norma]. Diuresis brought relief of the swelling and a weight loss of 5 lb. within 24 hr. We have tried to see as many patients as possible while they were suffering from this type of headache, and noted similar findings in other patients. Included in "emotional changes" was any mention of irritability, tension, nervousness, and constant fatigue, as well as depression (Fig. 4). A number of patients had these complaints before therapy, particularly as a part of a premenstrual tension syndrome, and remained the same or became worse while taking Ortho-Novum. Some experienced an improvement in emotional status while on therapy. In the clinic group, depression was seldom named. Rather, the patient described herself as being "miserable," "grouchy," "mad at everyone," etc. ,

60

50

Fig. 4. Incidence of emotional changes during therapy. IZ III U

II: III

20

Q.

10

A - ACTIVE CLINIC-1I4 B - ALL PRIVATE- 52 ~ EMOTIONAL CHANGES WHILE ON THERAPY ~ EMOTIONAL CHANGES BEFORE AND DURING THERAPY • EMOTIONAL STATUS IMPROVED

4.50

FERTILITY

CHERNICK

&

STERILITY

On the other hand, the private patient complained of "constant premenstrual tension," "irritability," and actual "depression." Six private patients discontinued the medication because of this depression; 1 was allowed to resume therapy. Another complained that after a year on Ortho-Novum she became "grouchy and irritable." In the ensuing 6 months, these symptoms became worse until she was "throwing things, crying all the time, and feeling very depressed." On the 1 cycle during which she had not been taking the pills, she felt better ("not irritable or weepy"). She commented that she has always been "highly strung" but seemed much worse while taking OrthoNovum. She also described herself as having been "very depressed" during her first pregnancy, when she had toxemia. Of the patients who noted an improvement in emotional state while on this medication, those attending the clinic often described themselves as "never having had such peace of mind" or as "being relaxed" because they "no longer have a constant fear of pregnancy." The private patients described themselves as no lon~er having premenstrual tension or as experiencing a general feeling of well-being. There were various reasons for discontinuing medication (Table 2). TABLE 2. Patients Discontinuing ME Depression No. Cycle

Hypertension No. Cycle

Varico.~e

Menorrhagirt No. Cycle

Dysmen. No. Cycle

veins No. Cycle

Family pressure

Confused

No. Cycle

No. Cycle CLINIC

1

0

10

1

0

5

1 2

2

3 1 1 1 1

0

.5

1

2 1

1

8

13

1

22

1

22

1 1 1

7 8 1:3

1

2

1

2

1 1

2 6

o

PA'

1 3

...

i)

8 9 10 12 22

PRIVATE

2

f

PK

VOL.

16, No.4, 1965

45l

ESTROGEN-PROGESTIN SIDE EFFECTS

Very few patients discontinued medication because of the above side effects. Six private patients stopped therapy because of depression; 1 is included in the surgery group, and another resumed therapy. One private patient, a nurse, stopped taking the pills because she found that her blood pressure had become markedly elevated while she was taking them. One clinic patient, an Indian woman whose blood pressure was in the hypertensive range before starting therapy, had Ortho-Novum withdrawn in an attempt to persuade her to attend the appropriate clinic for the investigation of her hypertension. Another private patient, who developed the syndrome of headache, hypertension, edema, and weight gain, discontinued therapy for 3 months and has now resumed the medication. Two private patients left the study because of family pressure. One was the wife of a medical student who did not want her to take the pills. The other became upset by her mother's insistence that the pills were a male hormone which would masculinize her. One of the biggest disappointments in the use of this agent as a contraceptive, especially for our clinic population which so urgently needs a simple, reliable contraceptive, is seen in the number who could not cope 19

Medication and Reasons for Discontinuation Mole follow-up

!e IC

No. Cycle

Re .QuIa tion of cycle No. C]/de

Desire to conceive

Separated

No. Cycle

No. Cycle

No. Cycle

Sur.Qery

Unknown

No. Cycle

No. Cycle

PATIENTS

1 1

5 8

0

0

1 ]

1

fE

Moved

6 7 11

1 1 1

6 15 18

1 1 1 1 2 1

1 3 6 8 19 29

5 2 2 4 1 1 1 3 1 1 1

2 5 7 8 9 10 11 12 14 16 18

1 1 1 1 1

8 10 14 17 19

1

22

1 1 1

3 4 17

PATIENTS

0

1

3

2 2 1 1 1

3 11 12 18 24

0

452

CHERNICK

FERTILITY

& STERILITY

with the method. Two of these women could not really understand the instructions well enough to manage. Three of our active patients needed monthly guidance. The other 9 women ill this group exhausted their supply of pills at variable times before returning for more, and were pregnant by the time they did appear; 1 did not bother to keep further clinic appointments. A further 17 women were fortunate enough not to become pregnant in 5-8 weeks without medication. DISCUSSION

In the past year we have noted 4 reports on the use of Ortho-Novum which have discussed side effects and acceptability.3, 4, 6, 8 In our series, nausea occurred in 8.7% of patients, usually in the first few days of medication, and not severe enough to cause any patient to withdraw. The incidence was almost ~~ that occurring in the one other study which also used the 5-mg. tablet1 and about ~~ of that reported in studies using the 2-mg. tablet. 3. 6, 8 An incidence of breakthrough bleeding of 27% was similar to that occurring in all other series. Except in 3 cases, breakthrough bleeding was limited to minimal spotting on 1 or 2 intermenstrual days. Two patients in our study complained of tender varicose veins, and 2 others developed a superficial phlebitis which responded to conservative management. We did not exclude any patient from participating in the study because of the presence of varicosities; 23 women with marked varicosities, some with a past history of phlebitis, have experienced no difficulties while taking Ortho-Novum. The incidence of weight gain in our study was at least 3 times that reported for patients taking the 2-mg. tablet. The incidence of bloating wa<; also increased. It is interesting to note that in 2 of the other series, both consisting entirely of private patients, depression was the reason for stopping medication in 8% of one group8 and 1.5% of another. 6 In our privatepatient series, the incidence of emotional disturbances characterized mainly by depression was 37%, and 6 of the 52 patiel!ts discontinued the medication for this cause. The parallel side effect was described as intense fatigue, which disappeared on discontinuing medication. In no case did the depression force discontinuation before the eighth cycle, and it occurred far more often between the fifteenth and twenty-second. It should be emphasized that, with this group, the investigators had evinced considerable interest in this possible medication effect. These patients were mainly intelligent wives of medical or paramedical men. Obviously the more the various side effects are emphasized, the more likely it is that the patient will look for them. Thus bias may well have been caused in the study.

VOL.

16, No.4, 1965

ESTROGEN-PROGESTIN SIDE EFFECTS

453

The occurrence of hypertension and the syndrome resembling toxemia of pregnancy was reported by Brownrigg in a case of pseudopregnancy induced by norethynodrel treatment of endometriosis. This report aroused our interest in this problem and we saw our first such case, using the norethindrone compound, about a month later. Improvement in menstrual function, in almost all the patients previously suffering from dysmenorrhea or menorrhagia, has been gratifying. However, the 9 women who experienced amenorrhea while taking the medication were distressed by this development, although they had been warned that amenorrhea might occur and would not mean pregnancy. When the 19-nor steroids were first used in clinical trials, there was some concern that they might induce hirsutism. In a preliminary report, Casey et al. indicate that the estrogenic properties of the compounds now in use actually reduce the rate of hair growth. One of the private patients in our study recently volunteered the information that hair growth on her legs had decreased considerably since she started taking Ortho-Novum for contraception. A new area of use for this drug may lie in the treatment of idiopathic hirsutism. Future Studies

We are at present studying a control group of women not receiving medication, to determine the incidence of these side effects in the normal menstrual cycle. We plan parallel studies of body water and its distribution in both our study and control groups. We have begun other determinations of body composition which we hope will give us a better understanding of the problem of weight gain. Because we have seen such striking examples of a syndrome similar to toxemia of pregnancy, we hope eventually to determine whether the appearance of this syndrome on progestational medication indicates a diathesis for its development during pregnancy. Further study is also needed to determine whether a previous history of emotional disturbance predisposes the patient to the development of depression during progestational therapy. SUMMARY AND CONCLUSIONS

Norethindrone 5 mg., mestranol 75 ""g. (Ortho-Novum) was administered cyclically to 221 clinic and 52 private patients. Weight gain and recorded blood-pressure elevation were more frequent in the clinic patients, and depression was more marked in the private patients. Further investigation is in progress to determine whether these side

454

CHERNICK

FERTILITY & STERILITY

effects are due to water retention caused by this estrogen-progestin compound. Further refinements in the medication to eliminate these side effects will increase its acceptability as a contraceptive for the sophisticated patient. At present, its advantages as an esthetic and reliable contraceptive outweigh the discomforts of the side effects for the highly motivated woman, particularly if she has experienced failure of other methods. However, the therapeutic value of Ortho-Novum in treatment of menstrual disorders seems to outweigh its performance as a method of conception control without unpleasant side effects. The modem woman, acutely conscious of her emotional and somatic responses, and perhaps too well informed about imaginary dangers, must have a method which does not disturb her emotionally or physically. A still simpler method must also be devised to meet the contraceptive needs of the many women unable to comprehend the complexity of cyclic medication. University of Western Ontario London, Ont., Ganada

REFERENCES 1. BROWNRIGG, C. M. Toxaemia in hormone-induced pseudopregnancy. Ganad. M. A. I. 87:408, 1962. 2. CASEY, J. H., MOXHAM, A., and NABARRO, J. D. N. Idiopathic hirsutism. Lancet 1:587, 1964. 3. CROCKER, K. M., and STITT, W. D. Ovulation inhibitors. Ganad. M. A. I. 90:713, 1964. 4. DICKINSON, J. H., and SMITH, C. C. A new and practical oral contraceptive agent: norethindrone with mestranol. Ganad. M. A. J. 89:242, 1963. 5. KINCH, R. A. H. Toxemia as a cause of maternal death. Glin. Obst. & Cynec. 6:842, 1963. 6. RINGROSE, C. A. D. Current concepts in conception control. Ganad. M. A. I. 89:246, 1963. 7. SWARTZ, D. P., WALTERS, J. H., PLUNKETT, E. R., and KINCH, R. A. H. Clinical experience with a new oral contraceptive. Fertil. & Steril. 14:320, 1963. 8. WEARING, M. P. The use of norethindrone (2 mg.) with mestranol (0.1 mg.) in fertility control: a preliminary report. Ganad. M. A. J. 89:239, 1963.