Clinical study of a once-a-month oral contraceptive: Quinestrol-quingestanol

CONTRACEPTION

CLINICAL

STUDY OF A ONCE-A-MONTH ORAL CONTRACEPTIVE: QUINESTROL-QUINGESTANOL

Alfred0 Larranaga, Professor Universidad National Mayor de San Marcos, Lima, Peru, S.A. Edel Berman, Warner-Lambert Research Institute, Morris Plains, New Jersey, U.S.A.

ABSTRACT A combination of quinestrol, a long-acting estrogen, and quingestanol acetate, a progestin, given by mouth once every four weeks was found to be an effective contraceptive in 303 healthy, fertile women for 2,493 cycles. Menstrual cycle control was good with normal amount of flow and normal Withdrawal bleeding or slightly increased duration of flow. usually began 7 to 14 days after administration of quinestrolUndesirable effects were similar in type and quingestanol. frequency to those reported for conventional oral contraceptives.

Accepted

for

publication

January

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INTRODUCTION

Although oral contraceptives have been used successfully by poor and uneducated patients, there is a need for simpler techniques. Following the demonstration of the efficacy of quinestrol-quingestanol given once every four weeks by Maqueo,et al.(l) and by Guiloff,et a1.(2), we decided to study these drugs with some modifications to simplify the method even further.

METHODS Quinestrol, the 3-cyclopentyl ether derivative of ethinyl estradiol, is an estrogen which has prolonged activity in animals(3) and man(4,5) as a result of storage in and subsequent release from body fat(6,7,8). Quingestanol acetate, the 3-cyclopentyl enol ether derivative of norethindrone acetate, is a progestogen with twice the potency of and with the same biological profile as norethindrone acetate(9,lO). The study was done in 5 different clinics in Lima, Peru. Most patients were very poor and many were illiterate. A small number of private patients were seen at a private office. Our schedule of administration differed from that reported by Maqueo(1) and by Guiloff(2) as follows: Following history and examination and provided the patient was not pregnant and had no other contraindications to the use of quinestrol-quingestanol, the first doses of 2 mg quinestrol and 2.5 mg quingestanol acetate* were given on whatever day of the cycZe the patient was seen. Patients were asked to return to the clinic exactly four weeks later and the same doses of these drugs were repeated. Subsequent doses were given at intervals of 4 weeks; after 6 months of treatment, patients were given a 3 to 6 months' supply of drugs if there were no unusual problems. Early in the study, patients were advised to use an additional method of contraception until the second dose was given. After four first cycle pregnancies, however, it was decided to use quingestanol acetate in a dose of 300 mcg daily between the first and second doses. Quingestanol acetate has been reported to be an effective oral contraceptive at this dose level and does not inhibit ovulation in more than 50% of cycles(ll,l2). * The combination will be referred to as quinestroZ-quingestanol in this paper.

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Post-partum patients were started on 2 mg quinestrol and 2.5 mg quingestanol acetate 4 to 6 weeks after delivery and the same schedule of treatment was used as above except that quingestanol acetate 300 mcg daily was not used in the first 4 weeks of treatment. Twenty percent of patients were in the post-partum period and were lactating when quinestrol-quingestanol was started.

RESULTS Total experience amounted to 2,493 cycles for 303 patients of whom 73 patients have completed one year of treatment. The mean age of all patients was 29.1 years and they were very fertile with a mean of 5.2 pregnancies and a mean of 1.1 admitted abortions. Pregnancies Four patients became pregnant during treatment, all of them during the first month, for a rate of 1.9 per 100 woman years. Endometrial

Biopsies

One-hundred and seventy-nine endometrial biopsies were obtained at different times during the menstrual cycle in patients who had been treated for at least three months. Biopsies taken after the cessation of withdrawal bleeding and before the next dose of quinestrol-quingestanol were With increasing time interpreted as being proliferative. after quinestrol-quingestanol administration there was an increasing secretory response until the onset of withdrawal bleeding. Characteristics

of Withdrawal

Bleeding

Withdrawal bleeding began 6 to 13 days after administration of quinestrol-quingestanol in 66% of cycles (Figure 1) and became more predictable with increasing time of drug administration (Table I). Withdrawal bleeding followed the first dose in most patients, although post-partum patients The interval frequently missed the first menstrual flow. between administration of the first dose and the onset of withdrawal bleeding has been called "Cycle 0" in this paper.

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Figure

1

Table

I

WITHDRAWAL Interval (days 1 l-3

Cycle

O*

Cycle

INTERVAL

Percent of Patients Cycle Cycle 6 3

12

All Cycles

5.

1.

3.

0.

3.

4-13

58.

75.

75.

87.

73.

14-21

29.

15.

16.

13.

18.

8.

9.

7.

0.

6.

11.9

11.2

10.8

.22

Mean

(days)

9.7

Cycle length was generally regular on mean of 28.7 days (Figure 2). The percentage reporting a cycle length of between 26 and 33 progressive increase during the first year of (Table II).

140

treatment with of patients days showed a treatment

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Figure

Table

2

II

CYCLE LENGTH (Percent of Patients) Cycle

< 25 days

Pretreatment

26-33 days

> 34 days

5

94

1

0

37

40

23

2

29

52

18

5

21

61

19

11

21

72

8

The duration of withdrawal bleeding was increased by an average of about one day (Figure 3). The mean duration of flow varied from 5.4 to 6.5 days in different cycles of treatment.

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Figure

3

The duration of bleeding was reported as 7 days or longer in 35% of cycles after beginning treatment compared to 12% of cycles before-beginning treatment (Table III): about 10% of cycles were reported as lasting for 9 days or longer. This did not seem to be a problem; breakthrough or heavy bleeding was considered more inconvenient by patients. Endometrial biopsies in patients with excessively prolonqed bleedinq almost invariably showed proliferation without any secretory change.

Table

III

DURATION OF FLOW (Percent of Patients) Cycle

2 days or less

3 to 6 days

7 days or more

Pretreatment

5

82

12

0

7

69

25

4

3

62

35

7

3

60

37

14

0

77

23

Percent All cycles of treatment

142

3

of Cycles 61

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There was little change in the percentage of patients reporting heavy menstrual flow during the first few cycles but by the sixth cycle of treatment with quinestrol-quingestano 1, a much lower percentage reported heavy flow with a shift to average amount of flow (Table IV). Post-partum patients reported heavy flow more frequently in the first 3 or 4 cycles of treatment than patients who began treatment after the postpartum period although this could not be proved statistically.

Table

IV

AMOUNT OF FLOW (Percent of Patients) Cycle

Light

Pretreatment

Average

Heavy

16

63

19

0

21

61

18

2

20

62

19

5

17

74

9

11

10

81

10

Variable

2

Lactation Since only 20% of patients were lactating when they it is difficult to draw any began quinestrol-quingestanol, firm conclusions regarding the effect of these drugs on lacHowever, it is our impression that patients produced tation. less milk and stopped lactating sooner than they would have without quinestrol-quingestanol. Undesirable --

Effects

(Table V)

The most troublesome side effects were nausea and vomiting, but the incidence and severity decreased rapidly Nausea at most lasted for only two after the first cycle. Headdays after administration of quinestrol-quingestanol. ache, nervousness, dizziness and mucorrhea also occurred frequently after the first dose but the incidence declined rapidly thereafter.

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Table V UNDESIRABLE EFFECTS (Percent of patients reporting) Cycle 0 -----__

1

2

3

4

5

6

Nausea

29

14

7

7

3

6

6

Vomiting

17

2

0

0

1

1

0

Headache

68

16

17

16

16

12

13

Nervousness

71

2

2

2

2

2

1

Dizziness

39

3

3

2

3

3

2

Mucorrhea

84

3

3

5

3

4

3

5

0

0

0

0

0

0

Depression

Spotting (vaginal spotting not requiring a pad) and breakthrough bleeding (vaginal bleeding requiring use of a pad) were reported by 10 and 7% of patients respectively in Cycle 0 after starting quinestrol-quingestanol and decreased progressively to 5% and 0% respectively in cycle 11 (Table VI). Post-partum patients reported spotting and breakthrough bleeding more frequently than patients who began quinestrolquingestanol after the post-partum period although we could not show a statistically significant difference.

Table VI MENSTRUAL 1

2

10

10

11

7

12

11

8

0 _---_-Spotting Breakthrough Bleeding Missed Bleeding

144

PROBLEMS Cycle 3

4

5

6

9

10

8

6

6

7

6

4

4

8

4

2

3

1

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The mean body weight of patients was 60.6 kg at the first visit. There was no statistically significant change in mean body weight in any cycle compared to pre-treatment mean weight; as many patients gained as lost weight in different cycles. Acceptability

(Table VII)

Headache, menstrual problems, and nausea and vomiting were the most frequent reasons for dropping out of the study. After the first few cycles, however, few patients dropped out and the drugs were well tolerated.

Table VII REASONS

FOR WITHDRAWING

FROM STUDY

Percent 1.

Drug Related Breakthrough bleeding irregular cycles Headache Abdominal Nausea

2.

and 16 6

pain

and vomiting

4 4

Nervousness

3

Varices

1

Amenorrhea

1

Not Drug Related Trip Separated

7 from husband

Others 3.

of dropouts

Unknown

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DISCUSSION This study was done largely in the "barriadas" (slums) of Lima, Peru. It has been our experience that if a woman was not started on a contraceptive method at her first clinic visit she would not return or, if she did, might be Methods other than "The Pill" were not popular or pregnant. practical. For these reasons we decided to give the first dose of quinestrol-quingestanol at the very first visit if there were no contraindications. We realized that a number of patients might be given the first dose shortly after conception but considered that this was a risk worth taking in view of the large numbers of patients who would benefit. The menstrual cycle "fell into step" with administration of quinestrol-quingestanol without any problems. By giving quinestrol-quingestanol on a fixed time schedule and not in relation to the day of the menstrual cycle, a potential source of error was eliminated. If the day of drug administration were pegged to the first day of.bleeding as is done with conventional oral contraceptives, quinestrolquingestanol would have to be administered on or about day 20 of the cycle and it is likely that there would be numerous errors because patients would have to count from day 1 to day Simplifying this method 20 before taking the contraceptive. and taking the drugs exactly 3 weeks after the beginning of bleeding would not help much. There is the additional hazard that patients with delayed or missed bleeding might become pregnant as a result of delayed administration. These problems were all eliminated by giving quinestrol-quingestanol at fixed intervals. On the basis of experience reported by Guiloff(2),a high pregnancy rate was expected in the interval between the In the first and second doses of quinestrol-quingestanol. first few months of the study, patients were advised to use an additional method of contraception during the interval between the first and second doses, or to abstain from sexual intercourse. As expected, this was not very successful and For this reason all new patients four pregnancies resulted. were given quingestanol acetate 300 mcg to be taken daily for the four weeks after the first dose of quinestrol-quingestanoi The pregnancy there were no pregnancies after this change. rate of 1.9 per 100 woman-years for the study compares favorably with rates reported by other investigators when oral contraceptives were used in a comparable population. It should be stressed that in this study the first dose of quinestrol-quingestanol was given on any day of the menstrual cycle and that this schedule differs from that reported by Maqueo(1) and by Guiloff, yet the pregnancy rate in the early cycles of treatment was very acceptable.

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The usual recommendation for induction of withdrawal bleeding in a primed endometrium has been an injection of progesterone in oil or of an oral progestin given for four consecutive days. We have shown that a single dose of quingestanol acetate can produce secretory changes in a primed endometrium leading to adequate withdrawal bleeding. Biological studies have shown that quingestanol acetate is a potent, short-acting progestin similar in biological profile to norethindrone acetate(9,lO). The ratio of quinestrol to quingestanol acetate must be correct if adequate shedding of the endometrium is to follow and be accompanied by an Guiloff reported acceptable amount and duration of bleeding. an increased incidence of heavy bleeding in the early cycles of treatment with a dose of 2 mg quinestrol and 5 mg quingestanol acetate especially in women beginning treatment less In our study heavy bleeding than 2 months after delivery(2). was not a problem probably because we used a dose of 2.5 mg quingestanol acetate, and partly because fewer of our patients began treatment in the post-partum period. The duration of bleeding while taking quinestrolquingestanol was somewhat longer thdn before beginning Endometrial treatment but this did not cause many problems. biopsies showed little or no secretory activity when bleeding was very prolonged, and some of these patients were given a daily dose of 2.5 mg quingestanol acetate for a few days with rapid cessation of bleeding in most cases. Quinestrol-quingestanol is not the contraceptive of choice in post-partum and lactating women because of an increased incidence of intermenstrual bleeding and of heavy menstrual bleeding, and because the milk supply appears to With the schedule.and doses decrease in amount and duration. we have used, however, it has been an acceptable and successful Further study is recontraceptive in a deprived population. quired to define its place relative to intrauterine devices and other oral contraceptives in poor and uneducated patients.

References 1.

Maqueo-Topete, M., Berman, E., Soberon, J., and Calderon, Fertil. and Steril. J. J. Pill a Month Contraceptive. In press.

2.

Guiloff, E., Berman, E., Montiglio, A., Osorio, R. and Lloyd, C. W. Clinical Study of a Once-a-Month Oral Quinestrol-Quingestanol. Fertil. and Contraceptive: In press. Steril.

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3.

Giannina, T. and Meli, A. Prolonged Oestrogenic Activity in Rats after Single Oral Administration of Ethinyloestradiol-3-cyclopentyl Ether. J. Pharm. Pharmac. 21:271-272 (April) 1969.

4.

Bompiani, A. and Bubani, V. Preliminary Results with 3-Cyclopentyl Ether Ethynyl Estradiol in Neurocirculatory Folia Endocrinologica 14: Disorders of the Menopause. (Suppl. 6) 203-223, 1961.

5.

Epstein, J., Sobrero, A., Rodriguez, A., and Krocin-Karacek, J. A New Oral Estrogen with Unusual Properties. Clin. Res. 13:241 (April) 1965.

6.

Meli, A., Wolff, A., Honrath, W. L. The Mechanism by which 3-Etherification with Cyclopentyl Alcohol Enhances the Oral Activity of Ethynylestradiol. Steroids 2: 417-424 (October) 1963.

7.

Meli, A., Steinetz, B., Beach, V., Wolff, A., and Giannina, T. Biological and Chromatographic Evidence for the Storage of Ethynylestradiol-3Cyclopentyl Ether in Rat Brain. Proc. Sot. Exp. Biol. and Med. 119:602-606 (July) 1965.

8.

Williams, K. I. H., Layne, D. S., Hobkirk, R., Nilsen, M. and Blahey, P. R. Metabolism of Doubly Labelled Ethynylestradiol-3-Cyclopentyl-Ether in Women. Steroids 9:275-287 (March) 1967.

9.

Giannina, T., Steinetz, B. G., Rassaert, C. L., Biological Profile of McDougall, E. A. and Meli, A. Proc. Sot. Exp. Biol. and Med. Quingestanol Acetate. 131:781 (July) 1969.

10. Mischler, T., Gawlak, D., Giannina, T. and Meli, A. The Biological Profile of Three 19-Nor TestosteroneProc. Sot. Exp. Biol. and 3-Cyclopentyl En01 Ethers. Med. 132:323-327 (October) 1969. Personal

11. Maqueo-Topete,

M.

12. Rubio,

Personal

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Boris.

communication.

communication.

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